The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic–Ischemic Brain Injury

Ci a ion: Du an i, A.; Belda ain, G.;
Ál a ez, A.; Sb iscia, M.; Ca loni, S.;
Balduini, W.; Alonso-Alconada, D.
The Endocannabinoid Sys em as a
Ta ge o Neu op o ec ion/
Neu o egene a ion in Pe ina al
Hypoxic–Ischemic B ain Inju y.
Biomedicines 2023,11, 28.
h ps://doi.o g/10.3390/
biomedicines11010028
Academic Edi o : Wesley
M. Raup-Konsa age
Recei ed: 18 No embe 2022
Accep ed: 19 Decembe 2022
Published: 22 Decembe 2022
Copy igh : © 2022 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
biomedicines
Re iew
The Endocannabinoid Sys em as a Ta ge o
Neu op o ec ion/Neu o egene a ion in Pe ina al
Hypoxic–Ischemic B ain Inju y
And ea Du an i 1,* , Go ane Belda ain 2, An onia Ál a ez 2, Ma ilde Sb iscia 1, Sil ia Ca loni 1,
Wal e Balduini 1and Daniel Alonso-Alconada 2,*
1Depa men o Biomolecula Sciences, Uni e si y o U bino Ca lo Bo, 61029 U bino, I aly
2Depa men o Cell Biology and His ology, School o Medicine and Nu sing,
Uni e si y o he Basque Coun y (UPV/EHU), 48940 Leioa, Spain
*Co espondence: [email p o ec ed] (A.D.); [email p o ec ed] (D.A.-A.);
Tel.: +39-0722-303501 (A.D.); +34-946-013294 (D.A.-A.)
Abs ac :
The endocannabinoid (EC) sys em is a complex cell-signaling sys em ha pa icipa es in
a as numbe o biological p ocesses since he p ena al pe iod, including he de elopmen o he
ne ous sys em, b ain plas ici y, and ci cui epai . This neu omodula o y sys em is also in ol ed in
he esponse o endogenous and en i onmen al insul s, being o special ele ance in he p e en ion
and/o ea men o ascula diso de s, such as s oke and neu op o ec ion a e neona al b ain inju y.
Pe ina al hypoxia–ischemia leading o neona al encephalopa hy is a de as a ing condi ion wi h no
he apeu ic app oach apa om mode a e hypo he mia, which is e ec i e only in some cases. This
o e iew, he e o e, gi es a cu en desc ip ion o he main componen s o he EC sys em (including
cannabinoid ecep o s, ligands, and ela ed enzymes), o la e analyze he EC sys em as a a ge o
neona al neu op o ec ion wi h a special ocus on i s neu ogenic po en ial a e hypoxic–ischemic
b ain inju y.
Keywo ds:
endocannabinoid sys em; cannabinoid ecep o s; FAAH inhibi o s; MGL inhibi o s;
neona al b ain inju y; hypoxia–ischemia; neu op o ec ion; neu ogenesis
1. The Endocannabinoid Sys em
The endocannabinoid (EC) sys em is a cell-signaling sys em consis ing mainly o a
leas wo cannabinoid (CB) ecep o s, namely CB
1
and CB
2
, hei endogenous ligands, and
he enzymes esponsible o he syn hesis, anspo , and deg ada ion o endocannabinoids
(ECs) [
1
]. Changes in he exp ession o ac i i y o CB ecep o s, ligands, o enzymes a e
implica ed in many pa hological condi ions [
2
]. Neu ological diso de s such as anxie y,
dep ession, schizoph enia, neu odegene a i e (e.g., Pa kinson’s and Hun ing on’s disease),
and s oke- ela ed diso de s, oge he wi h os eopo osis, mul iple scle osis, neu opa hic
pain, cance , glaucoma, hype ension, and obesi y/me abolic synd ome a e jus he majo
diseases associa ed wi h pe u ba ions o he EC sys em [
3
]. Recen ly, i has been hypo he-
sized ha CB
2
ecep o ac i a ion may be also use ul o educe he in lamma o y esponse
induced by SARS-CoV-2 in ec ion, due o i s capaci y o amelio a e he p oduc ion o
cy okines esponsible o he pa hological phenomenon [4].
Howe e , changes in EC one a e some imes ansien and likely pa o he o ganism’s
compensa o y esponse mainly aimed a educing symp oms o slowing he p og ession
o pa hological condi ions. In he ne ous sys em, he ac i i y o he EC sys em also
appea s ela ed o neu op o ec ion, because o i s abili y o modula e he in ensi y and
ex en o a se ies o dange ous biological e en s in ol ed in he neu odegene a i e p ocess.
These include modula ion o glu ama e exci o oxici y [
5
] and oxida i e s ess [
6
], and a
educ ion in he in lamma o y esponse [
7
]. This scena io led o conside ing he EC sys em
Biomedicines 2023,11, 28. h ps://doi.o g/10.3390/biomedicines11010028 h ps://www.mdpi.com/jou nal/biomedicines
Biomedicines 2023,11, 28 2 o 19
as a po en ial a ge o de eloping new neu op o ec i e he apies [
3
]. Howe e , i is
no always clea whe he an inc eased ac i i y o he EC sys em can be consequen o a
highe biosyn he ic ac i i y o a educ ion in he me abolic deg ada ion o he endogenous
ligands. The e o e, a be e unde s anding o he ole and mechanisms unde lying EC one
al e a ions du ing he neu odegene a i e p ocess ep esen s key ac o s o de eloping
new he apeu ic agen s ac ing h ough his impo an modula o y sys em.
O e all, despi e he as amoun o knowledge acqui ed o e ime, he explo a ion o
he EC sys em s ill ep esen s a s imula ing goal. Indeed, he complexi y o i s s uc u es,
he species a iabili y o i s cha ac e is ics, and he o e lapping o pha macological a ge s,
s ill lea e open many ques ions and scien i ic oppo uni ies. This e iew aims o highligh
he po en ial ole o he EC sys em in he neu odegene a i e and neu o- epa a i e p ocesses
esul ing om hypoxic–ischemic insul s occu ing du ing b ain de elopmen . A summa y
o CB ecep o s, ligands, and ela ed enzymes is also epo ed.
1.1. Cannabinoid Recep o s
The e ec s associa ed wi h he endo and exocannabinoid compounds a e p ima ily
ela ed o hei in e ac ion wi h he CB
1
and CB
2
ecep o s, disco e ed some decades
ago [
8
–
10
] and cha ac e ized based on hei neu obiology signaling [
11
]. Thei in ol emen
in many physiological and pa hological e en s jus i ies he cen al ole ha hey play as a
possible he apeu ic key o many diseases. CB ecep o s can be s imula ed o an agonized
by di e en ligands and can also be modula ed h ough he inhibi ion o he enzymes
esponsible o he deg ada ion o hei endogenous ligands [
12
]. Un o una ely, he
in e ac ion o exocannabinoids wi h hese ecep o s, especially wi h he CB
1
sub ype, is also
associa ed wi h he psycho opic e ec s o many ec ea ional d ugs, including Cannabis,
he so-called new psychoac i e subs ances [13], and sma d ugs (SPICE and K2 . . . ) [14],
o o o he undesi able se ious e ec s o syn he ic agonis o an agonis d ugs [15–17].
CB
1
ecep o s a e abundan ly exp essed in he cen al ne ous sys em (CNS), pa icu-
la ly in he ce eb al co ex, hippocampus, basal ganglia, and ce ebellum. CB
2
ecep o s,
ins ead, a e mos ly exp essed in he immune sys em, pa icula ly in B and na u al kille
cells. Howe e , CB
2
ecep o s ha e been also ound in some dis ic s o he CNS [
18
]
and he CB
1
also pe iphe ally, albei a low le els [
11
]. Mo e de ailed in o ma ion on he
o igin, s uc u al aspec s, and signaling p ocesses media ed by CB
1
and CB
2
ecep o s a e
epo ed in [19,20].
Gene ally, he ac i a ion o CB ecep o s de e mines he inhibi ion o adenyla e cyclase,
wi h a consequen dec ease in he le els o cyclic adenosine monophospha e (cAMP),
a second messenge in ol ed in nume ous in acellula signaling and essen ial o he
egula ion o many cell unc ions. The e is also e idence ha he CB
1
ecep o , in addi ion
o ac ing on adenyla e cyclase, can be coupled o ion channels [
21
], con i ming he key ole
o CBs in inducing ac i a ion o dep ession o neu o ansmission [11].
Recen s udies ha e also e ealed he exis ence o “a ypical” EC ecep o s, i.e., he
ansien ecep o po en ial anilloid (TRPV) channels, in ol ed in he nocicep i e signal-
ing; he GRP55, G-p o ein coupled ecep o s esponsible o some independen CB
1
and
CB
2
esponses; he pe oxisome p oli e a o -ac i a ed ecep o gamma (PPAR-
γ
) ecep o s,
which a e physiologically in ol ed in glucose me abolism and insulin signaling, and also
in in lamma ion and pain; and he dopamine, adenosine, opioid, and 5-HT
1A
ecep o s [
22
].
1.2. Endocannabinoids
Endocannabinoids (ECs) a e endogenous lipidic compounds o med by a long-chain
polyunsa u a ed a y acid ail and a pola head con aining unc ional g oups such as amide,
es e , e he , o hyd oxy one. They bind o CB ecep o s bu , unlike mos neu o ansmi e s
ha a e syn hesized and s o ed in esicles; hei syn hesis om memb ane phospholipids
is on-demand and use-dependen [23,24].
ECs a e eleased om pos synap ic e minals in a Ca
2+
-dependen manne . A e
hei elease, hey ac i a e p esynap ic CB ecep o s usually h ough e og ade signaling,
Biomedicines 2023,11, 28 3 o 19
al hough non- e og ade signaling may occu [
24
]. The e og ade signaling mechanism is
esponsible o modula ing bo h sho - e m and long- e m neu oplas ici y [
25
]. The sho -
e m ype o modula ion (seconds) pa icipa es in p ocesses, such as depola iza ion-induced
supp ession o inhibi ion and depola iza ion-induced supp ession o exci a ion. This may
occu h ough he inhibi ion o Ca
2+
ol age-ga ed channels and he modula ion o he
synap ic elease o a ious neu o ansmi e s, including glu ama e and
γ
-aminobu y ic
acid (GABA) [
26
,
27
]. In addi ion, ECs a e also in ol ed in long- e m synap ic plas ici y
(in he o de o minu es) h ough a CB
1
epea ed s imula ion o hese b ain ci cui s [
24
].
This p ocess leads o he long- e m dep ession phenomenon, wi h he inal dec ease in
he glu ama e gic and GABAe gic synap ic ac i i y [
28
]. Thus, ECs may unc ion as a
polymodal signal in eg a o o allow he di e si ica ion o synap ic plas ici y in a single
neu on [
29
]. EC ecep o s, in pa icula hose in he CNS, can, he e o e, be po en ial d ug
a ge s o he p e en ion and ea men o neu ologic diso de s, such as b ain ischemia [
30
].
The bes -s udied ECs a e N-a achidonoyle hanolamine (anandamide and AEA, as seen
in Figu e 1) [
31
] and 2-a achidonoyl-sn-glyce ol (2-AG, as seen in
Figu e 1) [32,33]
, bu o he
a achidonic acid de i a i es (e.g., noladin e he , i odhamine, and N-a achidonoyldopamine)
can bind CB1and/o CB2 ecep o s, al hough hei physiological ole is no ye clea .
Biomedicines 2023, 11, 28 3 o 20
ECs a e eleased om pos synap ic e minals in a Ca2+-dependen manne . A e hei
elease, hey ac i a e p esynap ic CB ecep o s usually h ough e og ade signaling, al -
hough non- e og ade signaling may occu [24]. The e og ade signaling mechanism is
esponsible o modula ing bo h sho - e m and long- e m neu oplas ici y [25]. The sho -
e m ype o modula ion (seconds) pa icipa es in p ocesses, such as depola iza ion-in-
duced supp ession o inhibi ion and depola iza ion-induced supp ession o exci a ion.
This may occu h ough he inhibi ion o Ca2+ ol age-ga ed channels and he modula ion
o he synap ic elease o a ious neu o ansmi e s, including glu ama e and γ-aminobu-
y ic acid (GABA) [26,27]. In addi ion, ECs a e also in ol ed in long- e m synap ic plas-
ici y (in he o de o minu es) h ough a CB1 epea ed s imula ion o hese b ain ci cui s
[24]. This p ocess leads o he long- e m dep ession phenomenon, wi h he inal dec ease in
he glu ama e gic and GABAe gic synap ic ac i i y [28]. Thus, ECs may unc ion as a poly-
modal signal in eg a o o allow he di e si ica ion o synap ic plas ici y in a single neu on
[29]. EC ecep o s, in pa icula hose in he CNS, can, he e o e, be po en ial d ug a ge s
o he p e en ion and ea men o neu ologic diso de s, such as b ain ischemia [30].
The bes -s udied ECs a e N-a achidonoyle hanolamine (anandamide and AEA, as
seen in Figu e 1) [31] and 2-a achidonoyl-sn-glyce ol (2-AG, as seen in Figu e 1) [32,33],
bu o he a achidonic acid de i a i es (e.g., noladin e he , i odhamine, and N-a achi-
donoyldopamine) can bind CB1 and/o CB2 ecep o s, al hough hei physiological ole is
no ye clea .
Figu e 1. Chemical s uc u es o AEA and 2-AG.
AEA is a ull o pa ial agonis o he CB1 ecep o bu also shows low ac i i y o-
wa ds he CB2 ecep o [34–38], whe eas 2-AG is a ull agonis o bo h CB1 and CB2 ecep-
o s [39].
Di e ences be ween AEA and 2-AG occu also in he biosyn he ic pa hways espon-
sible o hei o ma ion and deg ada ion. Wi h e e ence o he syn he ic s ep, N-acyl
phospha idyle hanolamine phospholipase D (NAPE-PLD) [40,41] o diacylglyce ol lipase
(DGL) [42,43] a e he enzymes di ec ly in ol ed, whe eas a y acid amide hyd olase
(FAAH) [44–47] o monoglyce ide lipase (MGL) [48–50] a e he main enzymes esponsible
o hei me abolism, leading o he o ma ion o a achidonic acid and e hanolamine [51]
o glyce ol [52] ollowing a cellula in e naliza ion p ocess ca ied ou by speci ic ans-
po e s [53–55].
1.3. Cannabis, Phy ocannabinoids, and Syn he ic Cannabinoids
Cannabis con ains mo e han 500 compounds, o which a leas 100 a e known o be
phy ocannabinoids [56] owing o pha macological p ope ies [57]; hey a e desc ibed in
de ail in [58]. Paleobo anical s udies a es ha Cannabis was al eady p esen du ing he
Holocene epoch abou 11,700 yea s ago, mo e likely in he e i o ies o Cen al Asia nea
he Al ai Moun ains [59]. The i s w i en es imony on he use o Cannabis o he apeu ic
pu poses da es back o 2700 BC, when he Chinese empe o Shen-Nung epo ed a de-
ailed desc ip ion o i in a book ha la e became he Chinese compendium o d ugs [60].
Chinese people used his plan o diseases such as heuma ic pain, mala ia, cons ipa ion,
e c. [61]. Despi e hei long his o y, he phy ocannabinoids con ained in Cannabis we e
iden i ied only a ew decades ago and p og essi ely s udied bo h as single molecules and
as hei de i a i es, and also based on s uc u e–ac i i y ela ionship s udies [62].
O
N
H
OH
AEA
O
OOH
2-AG
OH
Figu e 1. Chemical s uc u es o AEA and 2-AG.
AEA is a ull o pa ial agonis o he CB
1
ecep o bu also shows low ac i i y owa ds
he CB
2
ecep o [
34
–
38
], whe eas 2-AG is a ull agonis o bo h CB
1
and CB
2
ecep o s [
39
].
Di e ences be ween AEA and 2-AG occu also in he biosyn he ic pa hways espon-
sible o hei o ma ion and deg ada ion. Wi h e e ence o he syn he ic s ep, N-acyl
phospha idyle hanolamine phospholipase D (NAPE-PLD) [
40
,
41
] o diacylglyce ol lipase
(DGL) [
42
,
43
] a e he enzymes di ec ly in ol ed, whe eas a y acid amide hyd olase
(FAAH) [
44
–
47
] o monoglyce ide lipase (MGL) [
48
–
50
] a e he main enzymes esponsible
o hei me abolism, leading o he o ma ion o a achidonic acid and e hanolamine [
51
]
o glyce ol [
52
] ollowing a cellula in e naliza ion p ocess ca ied ou by speci ic ans-
po e s [53–55].
1.3. Cannabis, Phy ocannabinoids, and Syn he ic Cannabinoids
Cannabis con ains mo e han 500 compounds, o which a leas 100 a e known o be
phy ocannabinoids [
56
] owing o pha macological p ope ies [
57
]; hey a e desc ibed in
de ail in [
58
]. Paleobo anical s udies a es ha Cannabis was al eady p esen du ing he
Holocene epoch abou 11,700 yea s ago, mo e likely in he e i o ies o Cen al Asia nea
he Al ai Moun ains [
59
]. The i s w i en es imony on he use o Cannabis o he apeu ic
pu poses da es back o 2700 BC, when he Chinese empe o Shen-Nung epo ed a de ailed
desc ip ion o i in a book ha la e became he Chinese compendium o d ugs [
60
]. Chinese
people used his plan o diseases such as heuma ic pain, mala ia, cons ipa ion, e c. [
61
].
Despi e hei long his o y, he phy ocannabinoids con ained in Cannabis we e iden i ied
only a ew decades ago and p og essi ely s udied bo h as single molecules and as hei
de i a i es, and also based on s uc u e–ac i i y ela ionship s udies [62].
Themos s udiedandcha ac e izedphy ocannabinoidsha ebeen
∆9
- e ahyd ocannabinol
(
∆9
-THC, Figu e 2) [
63
], which cons i u es he main psychoac i e compound o Cannabis,
and he non-psycho opic cannabidiol (CBD, Figu e 2) [
64
]. Despi e simila s uc u es, hei
pha macodynamic p ope ies deeply di e .
Biomedicines 2023,11, 28 4 o 19
Biomedicines 2023, 11, 28 4 o 20
The mos s udied and cha ac e ized phy ocannabinoids ha e been Δ9- e ahyd ocan-
nabinol (Δ9-THC, Figu e 2) [63], which cons i u es he main psychoac i e compound o
Cannabis, and he non-psycho opic cannabidiol (CBD, Figu e 2) [64]. Despi e simila
s uc u es, hei pha macodynamic p ope ies deeply di e .
Figu e 2. Chemical s uc u es o Δ9-THC and CBD.
Δ9-THC ac s as a pa ial agonis o he CB1 ecep o , which explains i s s ong psy-
choac i e ou comes inducing he e ad e ec s (hypo he mia, ca alepsy, hypolocomo ion,
and analgesia). These unwan ed e ec s make he medical use o he Δ9-THC s ongly e-
s ic ed despi e i s bene icial ac ion (neu op o ec i e, an i-in lamma o y, and an ispas-
modic), which depends on he ac i a ion o CB2 and PPAR-γ ecep o s [56]. In addi ion,
he ac i i y o he molecule is dependen on cell ype, ecep o exp ession, and he p es-
ence o ECs o o he agonis s [56,65].
Fo i s pa , CBD has a high a ini y on a se ies o a ge s, including CB1 and CB2,
GPR55, TRPV, PPAR-γ, 5-HT1A, dopamine, and opioid ecep o s, and also on ion chan-
nels, which con ibu es o he bene icial e ec s o Cannabis in diseases ela ed o a wide
ange o pa hologies (neu ological, ischemic s oke, in lamma o y, pain, e c.) [22,66,67].
Al hough Δ9-THC and CBD a e he bes -known and s udied phy ocannabinoids,
o he compounds ha e been elie ed in Cannabis owing o hei he apeu ic po en ial.
Among hese, he main ones a e epo ed below. (1) Cannabige ol (CBG), which is a non-
psycho opic de i a i e wi h a low a ini y o he CB1 and CB2, bu i is able o in e ac
wi h o he ecep o s, such as α2-ad ene gic, TRPs supe amily, and 5-HT1A, and o possess
a ious p ope ies (an ip oli e a i e, an ibac e ial, an ioxidan , e c.) [56]. (2) Canna-
bich omene (CBC), which ac s weakly wi h CB1 and CB2 ecep o s and is able o inhibi
AEA up ake, is he mos po en agonis o TRPA1 channels and possesses an inocicep i e
and an i-in lamma o y p ope ies in i o and in i o [56]. (3) Δ9-Te ahyd ocannabi a-
ine (Δ9-THCV), which is he n-p opyl analogue o Δ9-THC and ac s weakly wi h CB1 e-
cep o s and mo e po en ly wi h he CB2 ones. Howe e , i is also able o ac wi h o he
a ge s such as TRP, GPR6, GPR55, and D2 ecep o s and o exe ela ed pha macological
ac ions [56]. (4) Cannabinol (CBN), which is he i s phy ocannabinoid s uc u ally cha -
ac e ized; i s de i a i es a e conside ed as he oxida i e by-p oduc o he deg ada ion
p ocess o Δ9-THC and CBD [62,68]. I ac s as a pa ial agonis o CB1 and CB2 and exe s
neu op o ec i e, an iepilep ic, and analgesic p ope ies [68,69].
Syn he ic cannabinoids a e ligands ha bind o CB ecep o s and modula e hei ac-
i i y. Thei design and he s udies aimed o acqui e in o ma ion on he s uc u al equi e-
men s o es ablish in e ac ions wi h CB ecep o s. Mo eo e , he goal was also ela ed o
he unde s anding o he ole played by molecules ha bind wi h hese a ge s, he ole o
he a ge s hemsel es, and, mo e gene ally, he ole o he EC sys em, since syn he ic
cannabinoids can be conside ed ools o inc ease knowledge in he ield. As o na u al
ligands, he ole o syn he ic cannabinoids mus always be con ex ualized wi hin he si -
ua ion o a isk/bene i a io ha would de i e om hei use. In spi e o he la ge e o
in syn hesizing and cha ac e izing he pha macological p o ile o hese molecules, apa
om nabilone, he e a e cu en ly no d ugs on he ma ke con aining a syn he ic canna-
binoid, bu many o hem a e used o ec ea ional pu poses and a e included in he lis
o subs ances o abuse [15,70–73].
The s uc u al equi emen s ha allow syn he ic cannabinoids o in e ac wi h CB
ecep o s a e highly a iable, a si ua ion ha s ongly in luences hei pha macological
O
OH
D9-THC
OH
CBD
H
HHO
Figu e 2. Chemical s uc u es o ∆9-THC and CBD.
∆9
-THC ac s as a pa ial agonis o he CB
1
ecep o , which explains i s s ong psy-
choac i e ou comes inducing he e ad e ec s (hypo he mia, ca alepsy, hypolocomo ion,
and analgesia). These unwan ed e ec s make he medical use o he
∆9
-THC s ongly
es ic ed despi e i s bene icial ac ion (neu op o ec i e, an i-in lamma o y, and an ispas-
modic), which depends on he ac i a ion o CB
2
and PPAR-
γ
ecep o s [
56
]. In addi ion,
he ac i i y o he molecule is dependen on cell ype, ecep o exp ession, and he p esence
o ECs o o he agonis s [56,65].
Fo i s pa , CBD has a high a ini y on a se ies o a ge s, including CB
1
and CB
2
,
GPR55, TRPV, PPAR-
γ
, 5-HT
1A
, dopamine, and opioid ecep o s, and also on ion channels,
which con ibu es o he bene icial e ec s o Cannabis in diseases ela ed o a wide ange o
pa hologies (neu ological, ischemic s oke, in lamma o y, pain, e c.) [22,66,67].
Al hough
∆9
-THC and CBD a e he bes -known and s udied phy ocannabinoids,
o he compounds ha e been elie ed in Cannabis owing o hei he apeu ic po en ial.
Among hese, he main ones a e epo ed below. (1) Cannabige ol (CBG), which is a non-
psycho opic de i a i e wi h a low a ini y o he CB
1
and CB
2
, bu i is able o in e ac wi h
o he ecep o s, such as
α2
-ad ene gic, TRPs supe amily, and 5-HT
1A
, and o possess a i-
ous p ope ies (an ip oli e a i e, an ibac e ial, an ioxidan , e c.) [
56
]. (2) Cannabich omene
(CBC), which ac s weakly wi h CB
1
and CB
2
ecep o s and is able o inhibi AEA up-
ake, is he mos po en agonis o TRPA1 channels and possesses an inocicep i e and
an i-in lamma o y p ope ies
in i o
and
in i o
[
56
]. (3)
∆9
-Te ahyd ocannabi a ine
(
∆9
-THCV), which is he n-p opyl analogue o
∆9
-THC and ac s weakly wi h CB
1
ecep o s
and mo e po en ly wi h he CB
2
ones. Howe e , i is also able o ac wi h o he a ge s such
as TRP, GPR6, GPR55, and D
2
ecep o s and o exe ela ed pha macological ac ions [
56
].
(4) Cannabinol (CBN), which is he i s phy ocannabinoid s uc u ally cha ac e ized; i s
de i a i es a e conside ed as he oxida i e by-p oduc o he deg ada ion p ocess o
∆9
-
THC and CBD [
62
,
68
]. I ac s as a pa ial agonis o CB
1
and CB
2
and exe s neu op o ec i e,
an iepilep ic, and analgesic p ope ies [68,69].
Syn he ic cannabinoids a e ligands ha bind o CB ecep o s and modula e hei
ac i i y. Thei design and he s udies aimed o acqui e in o ma ion on he s uc u al
equi emen s o es ablish in e ac ions wi h CB ecep o s. Mo eo e , he goal was also
ela ed o he unde s anding o he ole played by molecules ha bind wi h hese a ge s,
he ole o he a ge s hemsel es, and, mo e gene ally, he ole o he EC sys em, since
syn he ic cannabinoids can be conside ed ools o inc ease knowledge in he ield. As o
na u al ligands, he ole o syn he ic cannabinoids mus always be con ex ualized wi hin
he si ua ion o a isk/bene i a io ha would de i e om hei use. In spi e o he la ge
e o in syn hesizing and cha ac e izing he pha macological p o ile o hese molecules,
apa om nabilone, he e a e cu en ly no d ugs on he ma ke con aining a syn he ic
cannabinoid, bu many o hem a e used o ec ea ional pu poses and a e included in he
lis o subs ances o abuse [15,70–73].
The s uc u al equi emen s ha allow syn he ic cannabinoids o in e ac wi h CB
ecep o s a e highly a iable, a si ua ion ha s ongly in luences hei pha macological
ac i i y, in pa icula o wha conce n agonism, an agonism, and, mo e a ely, in e se
agonism. I is in e es ing o conside , howe e , ha hei ac i i y some imes depends on he
expe imen al model used o hei cha ac e iza ion (e.g., an agonism s. in e se agonism).
An o e iew o hese ea u es and he he apeu ic po en ial o CB ligands a e p esen ed in
Re s. [74–79].
Biomedicines 2023,11, 28 5 o 19
The he apeu ic in e es o he d ugs ha bind o CB ecep o s is also p o ed by
he ma ke ed d ugs men ioned abo e. Cesame
®
(nabilone— he syn he ic dibenzopy an-
9-one analog o
∆9
-THC), adminis e ed o he imp o emen o chemo he apy-induced
nausea and omi ing (CINV) s a es in pa ien s no esponding o con en ional an ieme ic
he apies. Ma inol
®
(d onabinol— he syn he ic pu e isome (–)- ans-
∆9
-THC) is p esc ibed
o he same pu poses as he o me and also o appe i e s imula ion in pa ien s wi h
AIDS (acqui ed immune de iciency synd ome). Sa i ex
®
(
∆9
-THC and cannabidiol in
an app oxima e 1:1 ixed a io) is used o he symp oma ic elie o he pain and/o he
managemen o neu opa hic pain and spas ici y in adul s wi h mul iple scle osis and is
no esponsi e o o he an ispas ici y he apies. Mo e ecen ly, a new d ug con aining >
98% CBD and less han 0.15%
∆9
-THC (Epidiolex
®
) has been app o ed o he ea men
o seizu es associa ed wi h wo a e and se e e o ms o epilepsy (Lennox–Gas au and
D a e synd omes) in pa ien s wo yea s o age and olde [56,66,80,81].
An in iguing and in e es ing ea u e o CB ecep o ligands is ha hey a e able o
exe a neu op o ec i e ole a e ischemic inju ies [
82
–
85
]. The CB
1
and CB
2
agonis s
(–)-CP-55,940 [
86
] and (R)-(+)-WIN-55212-2 [
87
], he CB
1
in e se agonis s SR141716A [
88
]
and AM 251 [89], he CB1an agonis s LY320135 [90], and he CB2agonis /CB1an agonis
URB447 [91] (Figu e 3) a e he ela ed ools s udied.
Biomedicines 2023, 11, 28 5 o 20
ac i i y, in pa icula o wha conce n agonism, an agonism, and, mo e a ely, in e se
agonism. I is in e es ing o conside , howe e , ha hei ac i i y some imes depends on
he expe imen al model used o hei cha ac e iza ion (e.g., an agonism s. in e se ago-
nism). An o e iew o hese ea u es and he he apeu ic po en ial o CB ligands a e p e-
sen ed in Re s. [74–79].
The he apeu ic in e es o he d ugs ha bind o CB ecep o s is also p o ed by he
ma ke ed d ugs men ioned abo e. Cesame ® (nabilone— he syn he ic dibenzopy an-9-
one analog o Δ9-THC), adminis e ed o he imp o emen o chemo he apy-induced nau-
sea and omi ing (CINV) s a es in pa ien s no esponding o con en ional an ieme ic
he apies. Ma inol® (d onabinol— he syn he ic pu e isome (–)- ans-Δ9-THC) is p e-
sc ibed o he same pu poses as he o me and also o appe i e s imula ion in pa ien s
wi h AIDS (acqui ed immune de iciency synd ome). Sa i ex® (Δ9-THC and cannabidiol in
an app oxima e 1:1 ixed a io) is used o he symp oma ic elie o he pain and/o he
managemen o neu opa hic pain and spas ici y in adul s wi h mul iple scle osis and is
no esponsi e o o he an ispas ici y he apies. Mo e ecen ly, a new d ug con aining >
98% CBD and less han 0.15% Δ9-THC (Epidiolex®) has been app o ed o he ea men
o seizu es associa ed wi h wo a e and se e e o ms o epilepsy (Lennox–Gas au and
D a e synd omes) in pa ien s wo yea s o age and olde [56,66,80,81].
An in iguing and in e es ing ea u e o CB ecep o ligands is ha hey a e able o
exe a neu op o ec i e ole a e ischemic inju ies [82–85]. The CB1 and CB2 agonis s (–)-
CP-55,940 [86] and (R)-(+)-WIN-55212-2 [87], he CB1 in e se agonis s SR141716A [88] and
AM 251 [89], he CB1 an agonis s LY320135 [90], and he CB2 agonis /CB1 an agonis
URB447 [91] (Figu e 3) a e he ela ed ools s udied.
Figu e 3. Chemical s uc u es o neu op o ec i e CB ligands.
Despi e he he apeu ic use o d ugs con aining Cannabis and i s de i a i es o o
syn he ic ligands o CB ecep o s, p oblems ela ed o hei abuse emain open. Fo his
eason, molecules inhibi ing he deg ada ion o endogenous ligands may ep esen an in-
e es ing al e na i e o modula ing he EC sys em [92].
OH
OH
OH
(–)-CP-55,940
N
O
O
N
O
(R)-(+)-WIN-55212-2
NN
O
NH
N
Cl
Cl
X
SR141716A X = Cl
AM251 X = I
O
O
O
CN
O
LY320135
N
O
H2N
Cl
URB447
Figu e 3. Chemical s uc u es o neu op o ec i e CB ligands.
Despi e he he apeu ic use o d ugs con aining Cannabis and i s de i a i es o o
syn he ic ligands o CB ecep o s, p oblems ela ed o hei abuse emain open. Fo his
eason, molecules inhibi ing he deg ada ion o endogenous ligands may ep esen an
in e es ing al e na i e o modula ing he EC sys em [92].
1.4. FAAH and MGL Inhibi o s
These compounds inc ease AEA and 2-AG le els by inhibi ing hei in acellula
deg ada ion. The hypo hesis leading o he design and de elopmen o EC me abolism
inhibi o s is based on he ac ha , by blocking he deg ada ion o hese endogenous
media o s, we can inc ease hei concen a ions in he physiological dis ic s whe e hey
a e o med. By using his app oach, i may be possible o ob ain pha macological agen s
cha ac e ized by he absence o he psycho opic side e ec s ypical o CB
1
exogenous
ligands. Indeed, ECs a e syn hesized and eleased on-demand in a issue-speci ic and ime-

Biomedicines 2023,11, 28 6 o 19
dependen manne and inhibi o s o hei me abolic enzymes will cause an inc ease in EC
le els only whe e and when i is physiologically equi ed. In his way, he ac i a ion o CB
ecep o s is ob ained h ough endogenous ligands, bu i is p olonged o e ime. Se e al
pieces o e idence suppo his app oach. Fo example, i has been epo ed ha FAAH
knockdown mice show inc eased le els o AEA in he b ain and o he issues leading o
CB
1
ecep o -media ed analgesia [
93
,
94
], o a educ ion in anxie y symp oms wi hou he
appea ance o ca alepsy [95].
The possibili y o a ge ing he FAAH and MGL enzymes, he e o e, may ep esen an
impo an he apeu ic app oach o di e en pa hologies [
2
,
96
–
99
] and, e en i he e a e no
d ugs on he ma ke ye , s udies ca ied ou in his ega d a e p omising. Diso de s ela ed
o anxie y, pain, and ciga e e and cannabis smoking a e he main pa hological s a es in
which EC me abolism inhibi o s ha e been s udied [
2
], and clinical s udies a e in p og ess.
FAAH and MGL inhibi o s ha e also been conside ed pha macological ools o inc ease
in o ma ion on he ole o he EC sys em in neu odegene a ion/neu op o ec ion a e
ischemic inju ies [
100
–
105
]. The FAAH inhibi o URB597 [
95
,
106
–
113
] and MGL inhibi o s
URB602 [
101
,
114
–
116
], JZL184 [
117
], KML29 [
118
], and MJN110 [
119
] (Figu e 4) a e he
main expe imen al molecules assessed in hese s udies.
Biomedicines 2023, 11, 28 6 o 20
1.4. FAAH and MGL Inhibi o s
These compounds inc ease AEA and 2-AG le els by inhibi ing hei in acellula deg-
ada ion. The hypo hesis leading o he design and de elopmen o EC me abolism inhib-
i o s is based on he ac ha , by blocking he deg ada ion o hese endogenous media o s,
we can inc ease hei concen a ions in he physiological dis ic s whe e hey a e o med.
By using his app oach, i may be possible o ob ain pha macological agen s cha ac e ized
by he absence o he psycho opic side e ec s ypical o CB1 exogenous ligands. Indeed,
ECs a e syn hesized and eleased on-demand in a issue-speci ic and ime-dependen man-
ne and inhibi o s o hei me abolic enzymes will cause an inc ease in EC le els only
whe e and when i is physiologically equi ed. In his way, he ac i a ion o CB ecep o s
is ob ained h ough endogenous ligands, bu i is p olonged o e ime. Se e al pieces o
e idence suppo his app oach. Fo example, i has been epo ed ha FAAH knockdown
mice show inc eased le els o AEA in he b ain and o he issues leading o CB1 ecep o -
media ed analgesia [93,94], o a educ ion in anxie y symp oms wi hou he appea ance
o ca alepsy [95].
The possibili y o a ge ing he FAAH and MGL enzymes, he e o e, may ep esen
an impo an he apeu ic app oach o di e en pa hologies [2,96–99] and, e en i he e
a e no d ugs on he ma ke ye , s udies ca ied ou in his ega d a e p omising. Diso de s
ela ed o anxie y, pain, and ciga e e and cannabis smoking a e he main pa hological
s a es in which EC me abolism inhibi o s ha e been s udied [2], and clinical s udies a e in
p og ess. FAAH and MGL inhibi o s ha e also been conside ed pha macological ools o
inc ease in o ma ion on he ole o he EC sys em in neu odegene a ion/neu op o ec ion
a e ischemic inju ies [100–105]. The FAAH inhibi o URB597 [95,106–113] and MGL in-
hibi o s URB602 [101,114–116], JZL184 [117], KML29 [118], and MJN110 [119] (Figu e 4)
a e he main expe imen al molecules assessed in hese s udies.
Figu e 4. Chemical s uc u es o neu op o ec i e FAAH and MGL inhibi o s.
2. The Endocannabinoid Sys em in P ena al and Pos na al De elopmen
Du ing p ena al and pos na al b ain de elopmen , he EC sys em may play an ac i e
ole in he con ol o he cell cycle, p oli e a ion, su i al, and di e en ia ion o neu al
s em cells [120], as well as in he ma u a ion o he ne ous sys em and i s unc ions. The
modula ion o some o hese p ocesses appea s egula ed by he CB1 ecep o , which is
exp essed in he e y ea ly s ages o neu al de elopmen . Indeed, he exp ession o mem-
be s o he EC sys em has been desc ibed du ing ea ly de elopmen al and pos na al s ages
[121–123], and in he emb yonic a b ain, i s p esence was ound a ound day 11 o ges a-
ion [124]. In 1998, Be ende o e al. [121] no only demons a ed he exis ence o CB1
H
NO
O
ONH2
OH
N
O
URB597
URB602
O
O
OH
O
O
N
O O R
JZL184 R = p-NO2C6H5
KML29 R = CH(CF3)2
O
O
Cl
Cl
N
O
ON
N
MJN110
Figu e 4. Chemical s uc u es o neu op o ec i e FAAH and MGL inhibi o s.
2. The Endocannabinoid Sys em in P ena al and Pos na al De elopmen
Du ing p ena al and pos na al b ain de elopmen , he EC sys em may play an ac i e
ole in he con ol o he cell cycle, p oli e a ion, su i al, and di e en ia ion o neu al
s em cells [
120
], as well as in he ma u a ion o he ne ous sys em and i s unc ions.
The modula ion o some o hese p ocesses appea s egula ed by he CB
1
ecep o , which
is exp essed in he e y ea ly s ages o neu al de elopmen . Indeed, he exp ession o
membe s o he EC sys em has been desc ibed du ing ea ly de elopmen al and pos na al
s ages [
121
–
123
], and in he emb yonic a b ain, i s p esence was ound a ound day 11 o
ges a ion [
124
]. In 1998, Be ende o e al. [
121
] no only demons a ed he exis ence o CB
1
ecep o s, bu hey also showed ha hese ecep o s we e al eady unc ional in emb yonic
s ages. In humans, he p esence o CB
1
ecep o s has been documen ed as soon as a week
14 o ges a ion in he emb yo [125].
The egions in which CB
1
ecep o s a e exp essed in hese ea ly s ages, i.e., he co pus
callosum, s ia e minalis, s ia medulla is, asciculus e o lexum, o an e io commissu e,
a e ela ed o p ocesses such as cell p oli e a ion, mig a ion, axonal elonga ion and synap-
ogenesis [
121
–
123
,
126
]. The la e modi ica ions in CB
1
ecep o s’ loca ion du ing neu al
Biomedicines 2023,11, 28 7 o 19
de elopmen (becoming di e en in he adul b ain), sugges ha hei exp ession in he
b ain changes once hei con ibu ion o neu al de elopmen inishes [121,123].
In mu ine cell cul u es, CB
1
ecep o s appea in se e al cell ypes, including s em-like
cells, as ocy es, and imma u e neu ons [
127
]. I has also been obse ed ha he agonis (R)-
(+)-me hanandamide p omo ed sel - enewal, mul ipo ency, and neu onal di e en ia ion
ia CB
1
ac i a ion. When ECs a e p oduced o exogenously adminis e ed wi h bind CB
1
ecep o s, he
αi
subuni linked o he p o ein inhibi s he ac i i y o adenylyl cyclase and
he syn hesis o cAMP. Low le els o cAMP educe he ac i i y o he p o ein kinase-A
and, consequen ly, he ype-A po assium channels a e ac i a ed and lead o memb ane
hype pola iza ion. The
α0
subuni o he G p o ein associa ed wi h he CB
1
ecep o ,
ins ead, inhibi s ol age-dependen Ca
2+
channels causing cell depola iza ion. The
β
and
γ
subuni s, mo eo e , in e ac wi h pa hways, such as PI3K o PKB/Ak , ha ha e been
shown o induce he exp ession o ansc ip ion ac o s associa ed wi h cell p oli e a ion
(CREB, STAT-3, PAX-6, and
β
-ca enin). CB ecep o s a e also closely ela ed o neu al
sphingomyelinase, which gene a es ce amide om sphingomyelin loca ed in he plasma
memb ane, hus ac i a ing he syn hesis o ansc ip ion ac o s, such as ERK o p38, ha
con ol cell a e and su i al [
128
,
129
]. The in ol emen o ac o s, such as ERK o PI3K, in
neu ogenesis associa ed wi h CB1ac i a ion was also obse ed by Xapelli e al. [127].
The p ocesses o mig a ion and pa h- inding du ing neu ogenesis appea also pa ially
egula ed by he CB
1
ecep o . Thei blockage wi h a selec i e an agonis caused a dec ease
o 50% in mig a ion in a sc a ch wound assay in mouse e al co ex-de i ed cells [
130
]. The
same au ho s also labeled he os al mig a o y s eam explan s embedded in Ma igel
using he mig a ing neu oblas ma ke s PSA-NCAM and DCX, and obse ed a signi ican
educ ion (30%) in he mig a o y dis ance a e he ea men wi h a CB
1
ecep o an agonis .
The ole o he EC sys em in he pa h- inding unc ion also became e iden when EC signals
we e p o en o be behind axon di ec ion cues, helping neu ons ind hei pa h [131].
Toge he wi h CB ecep o s, he ECs AEA and 2-AG also make hei appea ance
in he p ena al pe iod. Despi e he p esence o AEA le els ha ing been de ec ed om
he ea ly s ages o he emb yo [
132
], 2-AG seems o be p edominan in he e al pe iod,
as his molecule has been ound in highe concen a ions han AEA [
133
]. Con e sely,
AEA le els inc ease g adually du ing b ain de elopmen un il an adul le el is eached,
while he concen a ion o 2-AG emains mo e o less s able han in he e al, young, and
adul b ains [122].
3. The Endocannabinoid Sys em as a Ta ge o Neu op o ec ion in
Hypoxic–Ischemic Encephalopa hy
Pe ina al HI leading o neona al encephalopa hy (NE) ep esen s a majo cause o dea h
and long- e m disabili y in neona es [
134
]. Each yea , up o 20,000 in an s a e a ec ed by NE
in Eu ope and e en mo e in egions wi h a lowe le el o pe ina al ca e [
135
]. Whe eas he
incidence o NE in Wes e n Eu ope and No h Ame ica is a ound 1.6/1000 e m bi hs [
136
],
neona al mo ali y is 6 imes highe in de eloping o low- esou ced coun ies compa ed
wi h de eloped o middle- o-high- esou ced coun ies.
Cu en ea men op ions o HI a e ex emely limi ed, making he managemen
o long- e m ou comes o i s p e en ion di icul . Ac ually, he only app o ed he apy
is he apeu ic hypo he mia, consis ing in lowe ing he body empe a u e o pa ien s o
33.5
◦
C o 72 h h ough cooling o ei he he whole body o jus he head [
137
]. The apeu ic
hypo he mia is ou inely implemen ed in he majo i y o i s -wo ld hospi als o ea
e m in an s wi h mode a e o se e e NE; howe e , cooling is only pa ially e ec i e as
a neu op o ec i e he apy (>45% o in an s ha e ad e se neu ode elopmen al ou comes
despi e ea men ) [
138
]. A he same ime, hypo he mia can de elop some po en ial side
e ec s due o he slowing o he mechanisms o clea ance and me abolism, he induced
immunosupp essi e ac i i y, and he inc ease in ene gy expendi u e esul ing om he
he mo egula o y esponse [
139
]. As he cu en cooling he apy p o ocols appea o be
Biomedicines 2023,11, 28 8 o 19
op imal [
140
], he e is an u gen need o imp o e neona al neu op o ec ion by de eloping
addi ional sa e and e ec i e neu op o ec i e ea men s [141,142].
The EC sys em is able o limi he dele e ious e ec s caused by mul iple oxic s imuli
such as glu ama e exci o oxici y, oxida i e s ess, and in lamma ion, hus p o iding neu-
op o ec ion in di e en pa adigms o b ain inju y [
84
,
143
]. The e o e, compounds ha
modula e he EC sys em could be p omising neu op o ec i e and/o neu ogenic agen s o
he ea men o CNS pa hologies, including NE.
The i s cannabinoid es ed in ce eb al ischemic models was he syn he ic CB
1
/CB
2
agonis (R)-(+)-WIN-55,212-2 [
144
]. The au ho s showed ha he exogenous adminis a ion
o his CB agonis signi ican ly educed he in a c olume and he loss o hippocampal
neu ons. They also s udied he neu op o ec i e e ec o cannabinoids du ing b ain de elop-
men and showed ha exogenous adminis a ion o he ECs AEA and 2-AG educed b ain
in a c ion in newbo n a s subjec ed o HI [
145
]. La e , some o he co-au ho s desc ibed he
neu op o ec i e and long-las ing bene icial e ec o URB602, an inhibi o o he deg ada ion
o 2-AG [
101
] in he same mu ine model. The neu op o ec i e e ec o cannabinoids was
also con i med in an expe imen al model close o he human condi ion, i.e., in he e al
lamb. In his model, he syn he ic cannabinoid agonis (R)-(+)-WIN-55,212-2 p o ec ed he
neona al b ain a e y low doses o main ain mi ochond ial in eg i y and unc ionali y [
146
],
o educe apop o ic cell dea h [147], and o amelio a e he in lamma o y esponse [148].
The classical way o modula e he EC sys em is h ough he ac i a ion o blockade o
CB
1
and CB
2
ecep o s, as desc ibed in he i s pa o his e iew. Howe e , CB
1
ecep o s
seem o play a dual ole in pos -ischemic neu onal damage, as he dec ease in glu ama e
elease due o CB
1
ac i a ion is accompanied by a pa allel dec ease in GABA elease,
esul ing in neu o oxici y ins ead o neu op o ec ion [
149
]. Mo eo e , CB
1
o e ac i a ion
in he pe ina al pe iod could be ha m ul [
150
] and his can limi he ansla ional in e es o
CB
1
agonis s. In addi ion, CB
1
-media ed psychoac i e e ec s [
151
], which a e unwan ed in
clinical ea men s, should also be conside ed.
Ac i a ion o he o he CB ecep o , he CB
2
, esul s in po en an i-in lamma o y
e ec s [
143
], and he CB
2
an agonism has no desc ibed bene icial e ec . A he apeu ic
app oach wi h d ugs in e ac ing wi h CB
2
ecep o s can be de eloped using ei he indi ec
(e.g., cannabidiol) o selec i e (e.g., GW405833) CB
2
agonis s. Ne e heless, cannabidiol
can induce se e e hypo ension [
152
] despi e being neu op o ec i e in di e en expe i-
men al pa adigms [
153
], whe eas GW405833 showed no p o ec ion a e HI [
154
]. This
e idence oge he wi h he inding ha he CB
1
an agonis /in e se agonis imonaban also
exe s a neu op o ec i e e ec , which adds u he complexi y o he e ec o cannabinoid-
in e ac ing compounds in neu odegene a ion.
Recen ly, some o he co-au ho s e alua ed he neu op o ec i e po en ial o he syn-
he ic cannabinoid URB447 [
85
]. URB447 is he i s mixed CB
1
an agonis and CB
2
agonis
ha binds o bo h CB
1
and CB
2
ecep o s wi h submic omola a ini y and good s e eoselec-
i i y [
91
]. URB447 s ongly educed b ain inju y when adminis e ed be o e HI in neona al
a s, bu mo e in e es ingly, he compound was e ec i e also when adminis e ed 30 min o
3 h a e he ini ial insul . URB447 educed ce eb al in a c ion by 95.7% (30 min) and 88%
(a 3 h) in he whole ipsila e al (damaged) hemisphe e.
Since a pha macological in e en ion wi hin 3 h a e he inju y is conside ed a clin-
ically easible he apeu ic window o ea pe ina al b ain inju y in humans [
155
], we
cha ac e ized he e ec o URB447 adminis e ed a his ime poin , ocusing on he con-
sequences o HI and URB447 adminis a ion on he ac i a ion o glial cells and whi e
ma e inju y. Toge he wi h a educ ion in as ogliosis and mic oglial ac i a ion, URB447
dec eased whi e ma e damage es o ing myelin basic p o ein le els 7 days a e HI,
con i ming he impo an ole played by he EC sys em in he neu odegene a i e and
neu o epa a i e p ocesses a e HI.
As commen ed abo e, nowadays, he only clinical he apy agains HI-induced NE
is mode a e hypo he mia, which exe s a numbe o neu op o ec i e esponses h ough
he educ ion in exci o oxici y, ee adical exposu e, blood–b ain ba ie dys unc ion, and
Biomedicines 2023,11, 28 9 o 19
delayed cell dea h [
156
]. Leke e al. [
157
] obse ed ha a single injec ion o he CB
1
syn he ic agonis HU-210 signi ican ly educed body empe a u e, con e ing a s ong
neu op o ec i e e ec o he hypoxic–ischemic a s, a bene icial e ec ha was los when
animals we e ea ed wi h he selec i e CB
1
an agonis SR141716. The enhancemen o
hypo he mia by s imula ing he EC sys em o by he combined he apy EC sys em plus
hypo he mia may ha e bene icial ou comes in neona es, so hese esponses a e cu en ly
unde in es iga ion in p eclinical models [158,159].
4. Can Endocannabinoid Sys em In e ac ing D ugs Modula e Neu ogenesis a e HI?
The disco e y o s em cells in he pos na al and adul mammalian b ain changed he
p e iously belie ed asse ion ha he adul b ain is unable o eplace los neu ons
[160,161]
.
Al hough s ill unknown wi h ce ain y in o he egions o he CNS, wo neu ogenic a -
eas pe sis a e bi h: he sub en icula zone (SVZ) o he la e al en icles and he
subg anula zone (SGZ) o he den a e gy us o he hippocampus [162–164].
The abili y o gene a e new neu ons and glial cells om hese niches may con ibu e
o he plas ici y o he newbo n b ain and issue emodeling a e damage [
165
–
169
]. Based
on hei egene a i e po en ial, cells om he SVZ o he en icles can be molecula ly ma-
nipula ed in si u o induce hei p oli e a ion and mig a ion o damaged si es o s imula ed
in i o
o la e ansplan a ion [
162
,
170
–
173
]. Howe e , he p ocesses o p oli e a ion,
mig a ion, di e en ia ion, and su i al will depend on a wide ange o ac o s, includ-
ing he ype, in ensi y, du a ion, and/o loca ion o he damage [
174
]. Thus, i is no ye
known whe he hese newly o med neu ons a e p ope ly in eg a ed in o he exis ing
neu al ne wo k and i hey can ep esen a ully unc ional mic oen i onmen a e a b ain
inju y [
175
]. I has been es ima ed ha 85% o he new neu ons gene a ed in esponse o
he insul do no su i e a e eaching ma u a ion [176].
The global damage induced by pe ina al HI may also a ec he neu ogenic niches
and hei neu o-p oli e a i e capaci y. A e 24–48 h om mode a e/se e e hypoxic–
ischemic damage, he SVZ may show ex ensi e cell dea h, p ima ily a ec ing neu onal
s em cells and also oligodend ocy e p ogeni o s [
177
,
178
]. In e es ingly, he neu ogenic
po en ial o his a ea can be a ec ed independen ly om cell dea h [
179
]. Indeed, in a
p eclinical model close o he human condi ion, i.e., newbo n pigle s, i has been shown ha
a dec eased cellula i y is associa ed wi h a educ ion in cell p oli e a ion and neu ogenesis
in he SVZ [
179
]. These e ec s occu ed wi hou nec o ic o apop o ic cell dea h 48 h a e
hypoxic–ischemic damage. Whe he his disc epancy could be ela ed o di e ences in he
se e i y/du a ion o he insul o he expe imen al model employed ( oden s. pigle )
emains he subjec o in es iga ion. I should also be conside ed ha he SVZ can p esen
sub- egional sensi i i y, wi h a eas and cell ypes showing selec i e ulne abili y o he
insul . Highe a es o su i al we e obse ed in i s medial zone [
180
] and in di e en
esponses o p e-oligodend ocy es and neu oblas s o hypoxic–ischemic damage [181].
Whe eas se e al wo ks poin ed owa d HI leading o dec eased cell p oli e a ion in
he SVZ ( o a e iew, see [
182
]), o he au ho s ha e desc ibed ha he inju ed ipsila e al
SVZ has he abili y o inc ease i s size a e a longe eco e y in e al [
176
,
178
,
183
,
184
], a
phenomenon a ibu ed o inc eased cell p oli e a ion [
176
,
185
]. Fo i s pa , he undamaged
con ala e al SVZ can also su e an expansion a e HI [
176
], wi h he mos undi e en ia ed
p ecu so s being esponsible o his inc ease in i s size [185].
The o he neu ogenic niche, he SGZ o he den a e gy us o he hippocampus, also
e ealed con lic ing esul s. Ba ley e al. [
186
] showed ha neu onal ( oge he wi h
mic oglial and endo helial) cell p oli e a ion was signi ican ly inc eased in he inju ed
ipsila e al hippocampus. The au ho s used a pos na al day 7 (P7) neona al mice model
subjec ed o pe manen unila e al ca o id liga ion plus 8% hypoxia o 75 min. Con e sely,
ea ly a e he publica ion o ha wo k, Kadam e al. [
187
] desc ibed ha o al coun s o new
cells we e signi ican ly lowe in bo h ipsila e al and con ala e al hippocampi, which in
u n co ela ed wi h lesion-induced a ophy. They used, howe e , a neona al s oke model
o unila e al ca o id liga ion alone o p oduce in a c s in P12 CD1 mice. In a mo e ecen
Biomedicines 2023,11, 28 16 o 19
118.
Chang, J.W.; Niphakis, M.J.; Lum, K.M.; Cogne a, A.B., III; Wang, C.; Ma hews, M.L.; Niessen, S.; Buczynski, M.W.; Pa sons,
L.H.; C a a , B.F. Highly selec i e inhibi o s o monoacylglyce ol lipase bea ing a eac i e g oup ha is bioisos e ic wi h
endocannabinoid subs a es. Chem. Biol. 2012,19, 579–588. [C ossRe ]
119.
Niphakis, M.J.; Cogne a, A.B.; Chang, J.W.; Buczynski, M.W.; Pa sons, L.H.; By ne, F.; Bu s on, J.J.; Chapman, V.; C a a , B.F.
E alua ion o NHS ca bama es as a po en and selec i e class o endocannabinoid hyd olase inhibi o s. ACS Chem. Neu osci.
2013
,
4, 1322–1332. [C ossRe ]
120.
Ga u i, A.-L.; Lada e, D.; Lenkei, Z. Type-1 cannabinoid ecep o signaling in neu onal de elopmen . Pha macology
2012
,90,
19–39. [C ossRe ]
121.
Be ende o, F.; Ga cia-Gil, L.; He nandez, M.L.; Rome o, J.; Cebei a, M.; de Miguel, R.; Ramos, J.A.; Fe nández-Ruiz, J.J.
Localiza ion o MRNA exp ession and ac i a ion o signal ansduc ion mechanisms o cannabinoid ecep o in a b ain du ing
e al de elopmen . De elopmen 1998,125, 3179–3188. [C ossRe ]
122.
Be ende o, F.; Sepe, N.; Ramos, J.A.; Di Ma zo, V.; Fe nández-Ruiz, J.J. Analysis o cannabinoid ecep o binding and mRNA
exp ession and endogenous cannabinoid con en s in he de eloping a b ain du ing la e ges a ion and ea ly pos na al pe iod.
Synapse 1999,33, 181–191. [C ossRe ]
123.
Rome o, J.; Ga cia-Palome o, E.; Be ende o, F.; Ga cia-Gil, L.; He nandez, M.L.; Ramos, J.A.; Fe nández-Ruiz, J.J. A ypical
loca ion o cannabinoid ecep o s in whi e ma e a eas du ing a b ain de elopmen . Synapse 1997,26, 317–323. [C ossRe ]
124.
Buckley, N.E.; Hansson, S.; Ha a, G.; Mezey, É. Exp ession o he CB
1
and CB
2
ecep o messenge nas du ing emb yonic
de elopmen in he a . Neu oscience 1997,82, 1131–1149. [C ossRe ] [PubMed]
125.
Biegon, A.; Ke man, I.A. Au o adiog aphic s udy o p e- and pos na al dis ibu ion o cannabinoid ecep o s in human b ain.
Neu oImage 2001,14, 1463–1468. [C ossRe ] [PubMed]
126.
Ma o, S.; Del Olmo, E.; Pazos, A. On ogene ic de elopmen o cannabinoid ecep o exp ession and signal ansduc ion
unc ionali y in he human b ain: On ogeny o CB1 ecep o s in human b ain. Eu . J. Neu osci. 2003,17, 1747–1754. [C ossRe ]
127.
Xapelli, S.; Agasse, F.; Sa dà-A oyo, L.; Be na dino, L.; San os, T.; Ribei o, F.F.; Vale o, J.; B agança, J.; Schi ine, C.; de Melo Reis,
R.A.; e al. Ac i a ion o ype 1 cannabinoid ecep o (CB
1
R) p omo es neu ogenesis in mu ine sub en icula zone cell cul u es.
PLoS ONE 2013,8, e63529. [C ossRe ]
128.
Díaz-Alonso, J.; Guzmán, M.; Gal e-Rope h, I. Endocannabinoids ia CB
1
ecep o s ac as neu ogenic niche cues du ing co ical
de elopmen . Philos. T ans. R. Soc. B Biol. Sci. 2012,367, 3229–3241. [C ossRe ]
129.
Fe nández-López, D.; Lizasoain, I.; Mo o, M.; Ma ínez-O gado, J. Cannabinoids: Well-sui ed candida es o he ea men o
pe ina al b ain inju y. B ain Sci. 2013,3, 1043–1059. [C ossRe ]
130.
Oudin, M.J.; Gajend a, S.; Williams, G.; Hobbs, C.; Lalli, G.; Dohe y, P. Endocannabinoids egula e he mig a ion o sub en icula
zone-de i ed neu oblas s in he pos na al b ain. J. Neu osci. 2011,31, 4000–4011. [C ossRe ]
131.
Be ghuis, P.; Rajnicek, A.M.; Mo ozo , Y.M.; Ross, R.A.; Mulde , J.; U bán, G.M.; Mono y, K.; Ma sicano, G.; Ma eoli, M.; Can y,
A.; e al. Ha dwi ing he b ain: Endocannabinoids shape neu onal connec i i y. Science 2007,316, 1212–1216. [C ossRe ]
132.
Pa ia, B.C.; Dey, S.K. Ligand- ecep o signaling wi h endocannabinoids in p eimplan a ion emb yo de elopmen and implan a ion.
Chem. Phys. Lipids 2000,108, 211–220. [C ossRe ]
133.
Fe nández-Ruiz, J.; Be ende o, F.; He nández, M.L.; Ramos, J.A. The endogenous cannabinoid sys em and b ain de elopmen .
T ends Neu osci. 2000,23, 14–20. [C ossRe ] [PubMed]
134.
Douglas-Escoba , M.; Weiss, M.D. Hypoxic-ischemic encephalopa hy: A e iew o he clinician. JAMA Pedia .
2015
,169, 397–403.
[C ossRe ]
135.
Maiwald, C.A.; Annink, K.V.; Rüdige , M.; Bende s, M.J.N.L.; an Bel, F.; Allegae , K.; Naulae s, G.; Bassle , D.; Klebe maß-
Sch eho , K.; Ven o, M.; e al. E ec o allopu inol in addi ion o hypo he mia ea men in neona es o hypoxic-ischemic
b ain inju y on neu ocogni i e ou come (ALBINO): S udy p o ocol o a blinded andomized placebo-con olled pa allel g oup
mul icen e ial o supe io i y (Phase III). BMC Pedia . 2019,19, 210. [C ossRe ]
136.
Lee, A.C.; Kozuki, N.; Blencowe, H.; Vos, T.; Bahalim, A.; Da ms ad , G.L.; Nie meye , S.; Ellis, M.; Robe son, N.J.; Cousens,
S.; e al. In apa um- ela ed neona al encephalopa hy incidence and impai men a egional and global le els o 2010 wi h
ends om 1990. Pedia . Res. 2013,74, 50–72. [C ossRe ] [PubMed]
137.
Da idson, J.O.; Wassink, G.; an den Heuij, L.G.; Benne , L.; Gunn, A.J. The apeu ic hypo he mia o neona al hypoxic–ischemic
encephalopa hy—Whe e o om he e? F on . Neu ol. 2015,6, 198. [C ossRe ] [PubMed]
138.
Edwa ds, A.D.; B ocklehu s , P.; Gunn, A.J.; Halliday, H.; Juszczak, E.; Le ene, M.; S ohm, B.; Tho esen, M.; Whi elaw,
A.; Azzopa di, D. Neu ological ou comes a 18 mon hs o age a e mode a e hypo he mia o pe ina al hypoxic ischaemic
encephalopa hy: Syn hesis and me a-analysis o ial da a. BMJ 2010,340, c363. [C ossRe ]
139.
Te o ou, K.; Sisa, C.; Iqbal, A.; Dhillon, K.; H is o a, M. Cu en he apies o neona al hypoxic–ischaemic and in ec ion-sensi ised
hypoxic–ischaemic b ain damage. F on . Synap ic Neu osci. 2021,13, 709301. [C ossRe ]
140.
Alonso-Alconada, D.; B oad, K.D.; Bainb idge, A.; Chand aseka an, M.; Faulkne , S.D.; Ke enyi, Á.; Hassell, J.; Rocha-Fe ei a, E.;
H is o a, M.; Fleiss, B.; e al. B ain cell dea h is educed wi h cooling by 3.5
◦
C o 5
◦
C bu inc eased wi h cooling by 8.5
◦
C in a
pigle asphyxia model. S oke 2015,46, 275–278. [C ossRe ]
141. Gonzalez, F.F. Neu op o ec ion s a egies o e m encephalopa hy. Semin. Pedia . Neu ol. 2019,32, 100773. [C ossRe ]
142.
Vic o , S.; Rocha-Fe ei a, E.; Rahim, A.; Hagbe g, H.; Edwa ds, D. New possibili ies o neu op o ec ion in neona al hypoxic-
ischemic encephalopa hy. Eu . J. Pedia . 2022,181, 875–887. [C ossRe ]

Biomedicines 2023,11, 28 17 o 19
143.
Fe nández-Ruiz, J.; Mo o, M.A.; Ma ínez-O gado, J. Cannabinoids in neu odegene a i e diso de s and s oke/b ain auma:
F om p eclinical models o clinical applica ions. Neu o he apeu ics 2015,12, 793–806. [C ossRe ] [PubMed]
144.
Nagayama, T.; Sino , A.D.; Simon, R.P.; Chen, J.; G aham, S.H.; Jin, K.; G eenbe g, D.A. Cannabinoids and neu op o ec ion in
global and ocal ce eb al ischemia and in neu onal cul u es. J. Neu osci. 1999,19, 2987–2995. [C ossRe ] [PubMed]
145.
La a-Celado , I.; Cas o-O ega, L.; Ál a ez, A.; Goñi-de-Ce io, F.; Lacalle, J.; Hila io, E. Endocannabinoids educe ce eb al
damage a e hypoxic–ischemic inju y in pe ina al a s. B ain Res. 2012,1474, 91–99. [C ossRe ] [PubMed]
146.
Alonso-Alconada, D.; Al a ez, F.J.; Al a ez, A.; Mielgo, V.E.; Goñi-de-Ce io, F.; Rey-San ano, M.C.; Caballe o, A.; Ma inez-
O gado, J.; Hila io, E. The cannabinoid ecep o agonis WIN 55,212-2 educes he ini ial ce eb al damage a e hypoxic–ischemic
inju y in e al lambs. B ain Res. 2010,1362, 150–159. [C ossRe ] [PubMed]
147.
Alonso-Alconada, D.; Ál a ez, A.; Ál a ez, F.J.; Ma ínez-O gado, J.A.; Hila io, E. The cannabinoid WIN 55212-2 mi iga es
apop osis and mi ochond ial dys unc ion a e hypoxia ischemia. Neu ochem. Res. 2012,37, 161–170. [C ossRe ]
148.
Alonso-Alconada, D.; Ál a ez, A.; A eaga, O.; Ma ínez-Iba güen, A.; Hila io, E. Neu op o ec i e e ec o mela onin: A no el
he apy agains pe ina al hypoxia-ischemia. In . J. Mol. Sci. 2013,14, 9379–9395. [C ossRe ]
149.
Pelleg ini-Giampie o, D.E.; Mannaioni, G.; Bage a, G. Pos -ischemic b ain damage: The endocannabinoid sys em in he
mechanisms o neu onal dea h: The endocannabinoid sys em in ce eb al ischemia. FEBS J. 2009,276, 2–12. [C ossRe ]
150.
Lomba d, C.; Hegde, V.L.; Naga ka i, M.; Naga ka i, P.S. Pe ina al exposu e o
∆9
- e ahyd ocannabinol igge s p o ound
de ec s in T cell di e en ia ion and unc ion in e al and pos na al s ages o li e, including dec eased esponsi eness o HIV
an igens. J. Pha macol. Exp. The . 2011,339, 607–617. [C ossRe ]
151.
Tu co e, C.; Blanche , M.-R.; La iole e, M.; Flamand, N. The CB
2
ecep o and i s ole as a egula o o in lamma ion. Cell. Mol.
Li e Sci. 2016,73, 4449–4470. [C ossRe ]
152.
Ga be g, H.T.; Solbe g, R.; Ba linn, J.; Ma inez-O gado, J.; Løbe g, E.-M.; Saugs ad, O.D. High-dose cannabidiol induced
hypo ension a e global hypoxia-ischemia in pigle s. Neona ology 2017,112, 143–149. [C ossRe ]
153.
Ma ínez-O gado, J.; Villa, M.; del Pozo, A. Cannabidiol o he ea men o neona al hypoxic-ischemic b ain inju y. F on .
Pha macol. 2021,11, 584533. [C ossRe ] [PubMed]
154.
Ri e s-Au y, J.R.; Smi h, P.F.; Ash on, J.C. The cannabinoid CB
2
ecep o agonis GW405833 does no amelio a e b ain damage
induced by hypoxia-ischemia in a s. Neu osci. Le . 2014,569, 104–109. [C ossRe ] [PubMed]
155.
Azzopa di, D.; S ohm, B.; Linsell, L.; Hobson, A.; Juszczak, E.; Ku inczuk, J.J.; B ocklehu s , P.; Edwa ds, A.D.; UK TOBY Cooling
Regis e . Implemen a ion and conduc o he apeu ic hypo he mia o pe ina al asphyxial encephalopa hy in he UK—Analysis
o na ional da a. PLoS ONE 2012,7, e38504. [C ossRe ] [PubMed]
156.
D u y, P.P.; Gunn, E.R.; Benne , L.; Gunn, A.J. Mechanisms o hypo he mic neu op o ec ion. Clin. Pe ina ol.
2014
,41, 161–175.
[C ossRe ]
157.
Leke , R.R.; Gai, N.; Mechoulam, R.; O adia, H. D ug-induced hypo he mia educes ischemic damage: E ec s o he cannabinoid
HU-210. S oke 2003,34, 2000–2006. [C ossRe ]
158.
Ba a a, L.; A uza, L.; Rod íguez, M.-J.; Aleo, E.; Vie ge, E.; C iado, E.; Sob ino, E.; Va gas, C.; Cep ián, M.; Gu ié ez-Rod íguez,
A.; e al. Neu op o ec ion by cannabidiol and hypo he mia in a pigle model o newbo n hypoxic-ischemic b ain damage.
Neu opha macology 2019,146, 1–11. [C ossRe ]
159.
La uen e, H.; Pazos, M.R.; Al a ez, A.; Mohammed, N.; San os, M.; A iz i, M.; Al a ez, F.J.; Ma inez-O gado, J.A. E ec s o
cannabidiol and hypo he mia on sho - e m b ain damage in new-bo n pigle s a e acu e hypoxia-ischemia. F on . Neu osci.
2016,10, 323. [C ossRe ]
160.
Ih ie, R.A.; Ál a ez-Buylla, A. Lake- on p ope y: A unique ge minal niche by he la e al en icles o he adul b ain. Neu on
2011,70, 674–686. [C ossRe ]
161.
Spalding, K.L.; Be gmann, O.; Alkass, K.; Be na d, S.; Salehpou , M.; Hu ne , H.B.; Bos öm, E.; Wes e lund, I.; Vial, C.; Buchholz,
B.A.; e al. Dynamics o hippocampal neu ogenesis in adul humans. Cell 2013,153, 1219–1227. [C ossRe ]
162.
Lois, C.; Al a ez-Buylla, A. P oli e a ing sub en icula zone cells in he adul mammalian o eb ain can di e en ia e in o neu ons
and glia. P oc. Na l. Acad. Sci. USA 1993,90, 2074–2077. [C ossRe ]
163.
E iksson, P.S.; Pe ilie a, E.; Bjö k-E iksson, T.; Albo n, A.-M.; No dbo g, C.; Pe e son, D.A.; Gage, F.H. Neu ogenesis in he adul
human hippocampus. Na . Med. 1998,4, 1313–1317. [C ossRe ] [PubMed]
164.
Ko nack, D.R.; Rakic, P. Cell p oli e a ion wi hou neu ogenesis in adul p ima e neoco ex. Science
2001
,294, 2127–2130.
[C ossRe ] [PubMed]
165.
As ican, B.; Paez-Gonzalez, P.; E b, J.; Kuo, C.T. Choline gic ci cui con ol o pos na al neu ogenesis. Neu ogenesis
2016
,
3, e1127310. [C ossRe ] [PubMed]
166.
Benne , E.J.; Luciano, D.; Jo, R.; Abdi, K.; Paez-Gonzalez, P.; Sheng, H.; Wa ne , D.S.; Liu, C.; E oglu, C.; Kuo, C.T. P o ec i e
as ogenesis om he SVZ niche a e inju y is con olled by no ch modula o Thbs4. Na u e 2013,497, 369–373. [C ossRe ]
167.
Faiz, M.; Sachewsky, N.; Gascón, S.; Bang, K.W.A.; Mo shead, C.M.; Nagy, A. Adul neu al s em cells om he sub en icula
zone gi e ise o eac i e as ocy es in he co ex a e s oke. Cell S em Cell 2015,17, 624–634. [C ossRe ]
168. Li neh, Y.; Adam, Y.; Miz ahi, A. Odo p ocessing by adul -bo n neu ons. Neu on 2014,81, 1097–1110. [C ossRe ]
169.
Sakamo o, M.; Ieki, N.; Miyoshi, G.; Mochima u, D.; Miyachi, H.; Imu a, T.; Yamaguchi, M.; Fishell, G.; Mo i, K.; Kageyama,
R.; e al. Con inuous pos na al neu ogenesis con ibu es o o ma ion o he ol ac o y bulb neu al ci cui s and lexible ol ac o y
associa i e lea ning. J. Neu osci. 2014,34, 5788–5799. [C ossRe ]
Biomedicines 2023,11, 28 18 o 19
170.
Gil-Pe o ín, S.; Du an-Mo eno, M.; Ceb ián-Silla, A.; Ramí ez, M.; Ga cía-Belda, P.; Ga cía-Ve dugo, J.M. Adul neu al s em
cells om he sub en icula zone: A e iew o he neu osphe e assay: A e iew o he neu osphe e assay. Ana . Rec.
2013
,296,
1435–1452. [C ossRe ]
171.
Kukeko , V.G.; Laywell, E.D.; Suslo , O.; Da ies, K.; Sche le , B.; Thomas, L.B.; O’B ien, T.F.; Kusakabe, M.; S eindle , D.A.
Mul ipo en s em/p ogeni o cells wi h simila p ope ies a ise om wo neu ogenic egions o adul human b ain. Exp. Neu ol.
1999,156, 333–344. [C ossRe ]
172.
Os en eld, T.; Tai, Y.-T.; Ma in, P.; Déglon, N.; Aebische , P.; S endsen, C.N. Neu osphe es modi ied o p oduce glial cell
line-de i ed neu o ophic ac o inc ease he su i al o ansplan ed dopamine neu ons: GDNF-modi ied ns imp o e neu on
su i al. J. Neu osci. Res. 2002,69, 955–965. [C ossRe ]
173.
Yu, S.-J.; Tseng, K.-Y.; Shen, H.; Ha ey, B.K.; Ai a aa a, M.; Wang, Y. Local Adminis a ion o AAV-BDNF o sub en icula zone
induces unc ional eco e y in s oke a s. PLoS ONE 2013,8, e81750. [C ossRe ] [PubMed]
174.
Chang, E.H.; Ado jan, I.; Mundim, M.V.; Sun, B.; Dizon, M.L.V.; Szele, F.G. T auma ic b ain inju y ac i a ion o he adul
sub en icula zone neu ogenic niche. F on . Neu osci. 2016,10, 332. [C ossRe ] [PubMed]
175.
Yu, T.-S.; Washing on, P.M.; Ke nie, S.G. Inju y-induced neu ogenesis: Mechanisms and ele ance. Neu oscien is
2016
,22, 61–71.
[C ossRe ] [PubMed]
176.
Plane, J.M.; Liu, R.; Wang, T.-W.; Sil e s ein, F.S.; Pa en , J.M. Neona al hypoxic–ischemic inju y inc eases o eb ain sub en icula
zone neu ogenesis in he mouse. Neu obiol. Dis. 2004,16, 585–595. [C ossRe ]
177.
Le ison, S.W.; Ro hs ein, R.P.; Romanko, M.J.; Snyde , M.J.; Meye s, R.L.; Vannucci, S.J. Hypoxia/ischemia deple es he a
pe ina al sub en icula zone o oligodend ocy e p ogeni o s and neu al s em cells. De . Neu osci.
2001
,23, 234–247. [C ossRe ]
178.
Niimi, Y.; Le ison, S.W. Pedia ic b ain epai om endogenous neu al s em cells o he sub en icula zone. Pedia . Res.
2018
,83,
385–396. [C ossRe ]
179.
Alonso-Alconada, D.; G essens, P.; Golay, X.; Robe son, N.J. Neu ogenesis is educed a 48 h in he sub en icula zone
independen o cell dea h in a pigle model o pe ina al hypoxia-ischemia. F on . Pedia . 2022,10, 793189. [C ossRe ]
180.
B azel, C.Y.; Ros i III, R.T.; Boyce, S.; Ro hs ein, R.P.; Le ison, S.W. Pe ina al hypoxia/ischemia damages and deple es p ogeni o s
om he mouse sub en icula zone. De . Neu osci. 2004,26, 266–274. [C ossRe ]
181.
Romanko, M.J.; Ro hs ein, R.P.; Le ison, S.W. Neu al s em cells in he sub en icula zone a e esilien o hypoxia/ischemia
whe eas p ogeni o s a e ulne able. J. Ce eb. Blood Flow Me ab. 2004,24, 814–825. [C ossRe ]
182.
Visco, D.B.; Toscano, A.E.; Juá ez, P.A.R.; Gou eia, H.J.C.B.; Guzman-Que edo, O.; To ne , L.; Manhães-de-Cas o, R. A sys ema ic
e iew o neu ogenesis in animal models o ea ly b ain damage: Implica ions o ce eb al palsy. Exp. Neu ol.
2021
,340, 113643.
[C ossRe ]
183.
Ong, J.; Plane, J.M.; Pa en , J.M.; Sil e s ein, F.S. Hypoxic-ischemic inju y s imula es sub en icula zone p oli e a ion and
neu ogenesis in he neona al a . Pedia . Res. 2005,58, 600–606. [C ossRe ] [PubMed]
184.
Yang, Z.; Le ison, S.W. Hypoxia/ischemia expands he egene a i e capaci y o p ogeni o s in he pe ina al sub en icula zone.
Neu oscience 2006,139, 555–564. [C ossRe ] [PubMed]
185.
Felling, R.J. Neu al s em/p ogeni o cells pa icipa e in he egene a i e esponse o pe ina al hypoxia/ischemia. J. Neu osci.
2006,26, 4359–4369. [C ossRe ] [PubMed]
186.
Ba ley, J.; Sol au, T.; Wimbo ne, H.; Kim, S.; Ma in-S udda d, A.; Hess, D.; Hill, W.; Walle , J.; Ca oll, J. B dU-posi i e cells in
he neona al mouse hippocampus ollowing hypoxic-ischemic b ain inju y. BMC Neu osci. 2005,6, 15. [C ossRe ] [PubMed]
187.
Kadam, S.D.; Mulholland, J.D.; McDonald, J.W.; Comi, A.M. Neu ogenesis and neu onal commi men ollowing ischemia in a
new mouse model o neona al s oke. B ain Res. 2008,1208, 35–45. [C ossRe ] [PubMed]
188.
Ziemka-Nalecz, M.; Jawo ska, J.; Sypecka, J.; Polowy, R.; Filipkowski, R.K.; Zalewska, T. Sodium bu y a e, a his one deace ylase
inhibi o , exhibi s neu op o ec i e/neu ogenic e ec s in a a model o neona al hypoxia-ischemia. Mol. Neu obiol.
2017
,54,
5300–5318. [C ossRe ] [PubMed]
189.
Buono, K.D.; Goodus, M.T.; Gua dia Clausi, M.; Jiang, Y.; Lopo chio, D.; Le ison, S.W. Mechanisms o mouse neu al p ecu so
expansion a e neona al hypoxia-ischemia. J. Neu osci. 2015,35, 8855–8865. [C ossRe ]
190.
Back, S.A.; Tuohy, T.M.F.; Chen, H.; Walling o d, N.; C aig, A.; S u e, J.; Luo, N.L.; Banine, F.; Liu, Y.; Chang, A.; e al. Hyalu onan
accumula es in demyelina ed lesions and inhibi s oligodend ocy e p ogeni o ma u a ion. Na . Med.
2005
,11, 966–972. [C ossRe ]
191.
Pendle on, J.C.; Shamblo , M.J.; Ga y, D.S.; Belegu, V.; Hu ado, A.; Malone, M.L.; McDonald, J.W. Chond oi in sul a e
p o eoglycans inhibi oligodend ocy e myelina ion h ough PTPσ.Exp. Neu ol. 2013,247, 113–121. [C ossRe ]
192.
Aguado, T.; Rome o, E.; Mono y, K.; Palazuelos, J.; Send ne , M.; Ma sicano, G.; Lu z, B.; Guzmán, M.; Gal e-Rope h, I. The CB
1
cannabinoid ecep o media es exci o oxici y-induced neu al p ogeni o p oli e a ion and neu ogenesis. J. Biol. Chem.
2007
,282,
23892–23898. [C ossRe ]
193.
Fe nández-López, D.; P adillo, J.M.; Ga cía-Yébenes, I.; Ma ínez-O gado, J.A.; Mo o, M.A.; Lizasoain, I. The cannabinoid
WIN55212-2 p omo es neu al epai a e neona al hypoxia–ischemia. S oke 2010,41, 2956–2964. [C ossRe ] [PubMed]
194.
B egy, A.; Nixon, R.; Lo ocki, G.; Alonso, O.F.; A kins, C.M.; Tsoul as, P.; B amle , H.M.; Die ich, W.D. Pos auma ic hypo he mia
inc eases doubleco in exp essing neu ons in he den a e gy us a e auma ic b ain inju y in he a . Exp. Neu ol.
2012
,233,
821–828. [C ossRe ] [PubMed]
195.
Silasi, G.; Colbou ne, F. The apeu ic hypo he mia in luences cell genesis and su i al in he a hippocampus ollowing global
ischemia. J. Ce eb. Blood Flow Me ab. 2011,31, 1725–1735. [C ossRe ] [PubMed]
Biomedicines 2023,11, 28 19 o 19
196.
Xiong, M.; Cheng, G.-Q.; Ma, S.-M.; Yang, Y.; Shao, X.-M.; Zhou, W.-H. Pos -ischemic hypo he mia p omo es gene a ion o neu al
cells and educes apop osis by Bcl-2 in he s ia um o neona al a b ain. Neu ochem. In .
2011
,58, 625–633. [C ossRe ] [PubMed]
197.
A é alo-Ma ín, Á.; Ga cía-O eje o, D.; Rubio-A aiz, A.; Gómez, O.; Molina-Holgado, F.; Molina-Holgado, E. Cannabinoids
modula e olig2 and polysialyla ed neu al cell adhesion molecule exp ession in he sub en icula zone o pos -na al a s h ough
cannabinoid ecep o 1 and cannabinoid ecep o 2: Cannabinoid ecep o s in pos -na al SVZ. Eu . J. Neu osci.
2007
,26, 1548–1559.
[C ossRe ] [PubMed]
198.
Iwai, M.; S e le , R.A.; Xing, J.; Hu, X.; Gao, Y.; Zhang, W.; Chen, J.; Cao, G. Enhanced oligodend ogenesis and eco e y o
neu ological unc ion by e y h opoie in a e neona al hypoxic/ischemic b ain inju y. S oke
2010
,41, 1032–1037. [C ossRe ]
[PubMed]
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