In e na ional Jou nal o
Molecula Sciences
Re iew
Mela onin: A Re iew o I s Po en ial Func ions and
E ec s on Den al Diseases
Ma ia Pe muy *, Mónica López-Peña, An onio González-Can alapied a and Fe nando Muñoz
Ana omy, Animal P oduc ion and Ve e ina y Clinical Sciences Depa men , Ve e ina y Facul y,
Uni e sidade de San iago de Compos ela, Campus Uni e si a io s/n, 27002 Lugo, Spain;
[email p o ec ed] (M.L.-P.); [email p o ec ed] (A.G.-C.); [email p o ec ed] (F.M.)
*Co espondence: [email p o ec ed]; Tel.: +34-982-82-2631
Academic Edi o : Russel Rei e
Recei ed: 17 Ma ch 2017; Accep ed: 13 Ap il 2017; Published: 19 Ap il 2017
Abs ac :
Mela onin is a ho mone syn hesised and sec e ed by he pineal gland and o he o gans.
I s sec e ion, con olled by an endogenous ci cadian cycle, has been p o en o exe immunological,
an i-oxidan , and an i-in lamma o y e ec s ha can be bene icial in he ea men o ce ain den al
diseases. This a icle is aimed a ca ying ou a e iew o he li e a u e published abou he use o
mela onin in he den al ield and summa ising i s po en ial e ec s. In his e iew a icle, an ex ensi e
sea ch in di e en da abases o scien i ic jou nals was pe o med wi h he objec i e o summa ising all
o he in o ma ion published on mela onin use in den al diseases, ocussing on pe iodon al diseases
and den al implan ology. Mela onin eleased in a na u al way in o he sali a, o added as an ex e nal
ea men , may ha e impo an implica ions o den al diso de s, such as pe iodon al disease, as
well as in he osseoin eg a ion o den al implan s, due o i s an i-in lamma o y and osseoconduc i e
e ec s. Mela onin has demons a ed o ha e bene icial e ec s on den al pa hologies, al hough u he
esea ch is needed o unde s and he exac mechanisms o his molecule.
Keywo ds: mela onin; o al ca i y; implan s; pe iodon al disease
1. In oduc ion
Mela onin (N-ace yl-5-me hoxy- yp amine) is an indoleamine syn hesised and sec e ed by he
pineal gland and o he o gans, such as he e ina, bone ma ow, and in es ines in a ci cadian pa e n.
Ex apineal si es con ibu e poo ly, o only upon speci ic s imuli o ci cula ing mela onin [
1
]. Mela onin
in luences nume ous physiological ac ions ha may be media ed by he binding o he indoleamine
o memb ane ecep o s in all issues [
2
,
3
]. Due o i s excellen lipophilic p ope ies, mela onin is
able o en e he subcellula compa men , inding i in high concen a ions in he nucleus and
he mi ochond ia o cells [
4
,
5
], being capable o bind o some cy osolic p o eins like kinase-C [
6
],
calmodulin [
7
] and cal e iculin [
8
]. Cu en ly, mela onin is no conside ed a ho mone in he classical
sense o he e m, because i is syn hesised in se e al o gans and does no exe e ec s on a speci ic
a ge [9], bu i is a he a powe ul cell p o ec o agains molecula damage.
Fo he syn hesis o mela onin, he pineal cells ake up yp ophan om he blood and, h ough
a hyd oxyla ion and a deca boxyla ion p ocess, u n i in o se o onin. Se o onin is hen con e ed
in o N-ace ylse o onin h ough N-ace yl ans e ase and subsequen ly me hyla ed o he inal o m o
mela onin by he enzyme hyd oxyindole-O-me hyl ans e ase [
10
,
11
] (Figu e 1). In heal hy indi iduals,
he maximum sec e ion o mela onin occu s be ween midnigh and 2 a.m., hen i dec eases o a
minimum du ing he day [
12
]. The p oduc ion o mela onin declines a e he age o 40–45 yea s, wi h
a con inuous educ ion as age inc eases [11].
In . J. Mol. Sci. 2017,18, 865; doi:10.3390/ijms18040865 www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2017,18, 865 2 o 13
In . J. Mol. Sci. 2017, 18, x 2 o 12
Figu e 1. Mela onin syn hesis and ep esen a ion o i s molecule (elabo a ed by he au ho s).
Se en y pe cen o he mela onin in blood is bound o p o eins and only he ee pe cen age
(30% o he o al mela onin) is able o di use in o he su ounding issues [1], including he o al
ca i y h ough sali a; hus, he p opo ion o plasma mela onin en e ing he o al ca i y ia he
sali a y glands anges om 24% o 33%, appea s o be s able [13] and he e a e no
mo pho-physiological ba ie s o mela onin; indole apidly c osses he blood-b ain ba ie , he
placen a, and all o he o he po en ial cellula impedimen s [14]. The e alua ion o he mela onin
le el in sali a is a eliable echnique o moni o ci cadian hy hms and mela onin sec e ion.
Mela onin has nume ous physiological unc ions in di e en pa s o he body, such as he
con ol o ci cadian hy hms [15,16], egula ion o body empe a u e [17], egula ion o sexual
de elopmen and he ep oduc i e cycle, especially in seasonal animals [18,19], and ac i a ion o he
immune sys em [20,21]. In he o al ca i y, mela onin has been ecognised as an impo an subs ance
wi h pa ac ine e ec s on nea by cells [22]; i also ac s as an an ioxidan and an an i-in lamma o y
and plays an impo an ole in bone o ma ion and in he educ ion o bone eso p ion.
Mela onin can be adminis e ed by se e al ou es (e.g., o ally, in ape i oneally, di ec ly in he
e ec -si e in den al implan s) and i is a ailable as a supplemen o as a p esc ip ion d ug,
depending on he coun y. This molecule has a long shel li e, is no expensi e, has ew side e ec s
compa ed o o he d ugs, and can be used wi h a e y wide sa e y ma gin. These cha ac e is ics,
along wi h he wide ange o e ec s on he issues, make i a po en ial he apy o di e en pu poses.
The aim o his e iew is o summa ise he po en ial ac ions o mela onin in he o al ca i y,
ocussing on implan ology and pe iodon al disease.
2. Ma e ial and Me hods
The PubMed da abase o he U.S. Na ional Lib a y o Medicine was used as he main elec onic
da abase in his e iew o he collec ion o da a, pe o ming a sys ema ic sea ch o he a icles
published in he li e a u e on he subjec . A comme cially a ailable so wa e p og am (Endno e,
Thomson Reu e s, London, UK) was used o elec onic i le managemen .
The combina ion o keywo ds used o he elec onic sea ch we e:
Figu e 1. Mela onin syn hesis and ep esen a ion o i s molecule (elabo a ed by he au ho s).
Se en y pe cen o he mela onin in blood is bound o p o eins and only he ee pe cen age (30%
o he o al mela onin) is able o di use in o he su ounding issues [
1
], including he o al ca i y
h ough sali a; hus, he p opo ion o plasma mela onin en e ing he o al ca i y ia he sali a y glands
anges om 24% o 33%, appea s o be s able [
13
] and he e a e no mo pho-physiological ba ie s o
mela onin; indole apidly c osses he blood-b ain ba ie , he placen a, and all o he o he po en ial
cellula impedimen s [
14
]. The e alua ion o he mela onin le el in sali a is a eliable echnique o
moni o ci cadian hy hms and mela onin sec e ion.
Mela onin has nume ous physiological unc ions in di e en pa s o he body, such as he con ol
o ci cadian hy hms [
15
,
16
], egula ion o body empe a u e [
17
], egula ion o sexual de elopmen
and he ep oduc i e cycle, especially in seasonal animals [
18
,
19
], and ac i a ion o he immune
sys em [
20
,
21
]. In he o al ca i y, mela onin has been ecognised as an impo an subs ance wi h
pa ac ine e ec s on nea by cells [
22
]; i also ac s as an an ioxidan and an an i-in lamma o y and plays
an impo an ole in bone o ma ion and in he educ ion o bone eso p ion.
Mela onin can be adminis e ed by se e al ou es (e.g., o ally, in ape i oneally, di ec ly in he
e ec -si e in den al implan s) and i is a ailable as a supplemen o as a p esc ip ion d ug, depending
on he coun y. This molecule has a long shel li e, is no expensi e, has ew side e ec s compa ed o
o he d ugs, and can be used wi h a e y wide sa e y ma gin. These cha ac e is ics, along wi h he
wide ange o e ec s on he issues, make i a po en ial he apy o di e en pu poses.
The aim o his e iew is o summa ise he po en ial ac ions o mela onin in he o al ca i y,
ocussing on implan ology and pe iodon al disease.
2. Ma e ial and Me hods
The PubMed da abase o he U.S. Na ional Lib a y o Medicine was used as he main elec onic
da abase in his e iew o he collec ion o da a, pe o ming a sys ema ic sea ch o he a icles
published in he li e a u e on he subjec . A comme cially a ailable so wa e p og am (Endno e,
Thomson Reu e s, London, UK) was used o elec onic i le managemen .
In . J. Mol. Sci. 2017,18, 865 3 o 13
The combina ion o keywo ds used o he elec onic sea ch we e:
•mela onin
•mela onin and o al ca i y
•mela onin and implan
•mela onin and pe iodon al disease
•mela onin and cance
•mela onin and mic oo ganisms, bac e ia o i us
The ob ained esul s we e ca e ully e alua ed and he mos impo an indings ela ed o he use
and e ec s o mela onin on o al diseases a e summa ised below.
Fo a be e unde s anding o he esul s, he p esen e iew was di ided in o he
ollowing sec ions:
1. Main e ec s o mela onin ela ed o he o al ca i y;
2. Mela onin and den al implan s;
3. Mela onin and pe iodon al disease;
4. O he e ec s o mela onin on he o al ca i y.
3. Resul s
3.1. Main E ec s o Mela onin Rela ed o he O al Ca i y
The ole o mela onin in he o al ca i y (bo h in physiological and pa hological p ocesses) is
basically ela ed o i s an ioxidan and an i-in lamma o y e ec s, as well as ac ing as a media o in
bone o ma ion and eso p ion [23].
F ee adicals a e molecules wi h an unpai ed elec on in hei alence shell. Due o his
elec on-de icien s a e, hey a e highly eac i e, causing damage o he adjacen molecules by
abs ac ing an elec on o dona ing i o hem. Ou o all he ee adicals, hose de i ed om oxygen o
ni ogen could be highly des uc i e; gi en ha mos o he cells a e o an ae obic na u e, hey gene a e
eac i e oxygen o ni ogen species (ROS and RNS), he an ioxidan sys em media ed by enzymes o
small molecules ha can sca enge hose ee- adicals being pa icula ly impo an unde physiological
condi ions [
24
]. Mela onin was p o en o di ec ly neu alise ROS [
25
,
26
] ac ing as an an ioxidan in
se e al condi ions and issues.
Due o i s an ioxidan p ope ies and i s abili y o de oxi y ee adicals, mela onin can also
in e e e in he bone eso p ion p ocess, media ed by he os eoclas s ac ing a he le el o he os eoclas
lacuna and blocking he eac i e oxygen species p oduced by he supe oxide dismu ase [
27
]. Ano he
e ec o mela onin in bone eso p ion is media ed h ough he down egula ion o he ecep o ac i a o
o nuclea ac o
κ
-B ligand (RANKL)-media ed os eoclas o ma ion and ac i a ion, which inc eases
bone mass. This e ec was achie ed wi h pha macological doses o mela onin [28].
Wi h ega d o bone o ma ion, mela onin p omo es os eoblas di e en ia ion [
29
–
31
] and
s imula es he o ma ion o a new mine alised ma ix [
29
,
32
]. I was obse ed ha , in human
os eoblas s
in i o
, mela onin has he abili y o s imula e, a mic omola concen a ions, he
p oli e a ion and syn hesis o collagen ype I, o he bone ma ix p o eins and bone ma ke s (including
alkaline phospha ase, os eopon in, and os eocalcin). I also educes he os eoblas di e en ia ion
pe iod om he usual 21 days o 12 [
29
,
32
]. Ano he s udy has shown ha mela onin in luences
p ecu so s o bone cells in he bone ma ow o a s [
33
] and p o ec s he bone cells om oxida i e
a acks [34].
Mela onin also has o he e ec s on bone, di e en om hose o o ma ion and eso p ion,
such as ac ing as a signi ican modula o o calcium me abolism, p e en ing os eopo osis and
hypocalcaemia [35].
Ano he ole o mela onin, impo an o bone egene a ion, is ha o media o o
angiogenesis [
36
]. G ow h ac o s, such as he ascula endo helial g ow h ac o (VEGF), a e
In . J. Mol. Sci. 2017,18, 865 4 o 13
conside ed po en ial angiogenic modula o s. Mela onin inc eases VEGF exp ession by exe ing a
signi ican p o-angiogenic ac i i y in issues, including bone [
37
]. In ano he s udy, mela onin also
showed a posi i e e ec on monocy es, cy okines, and ib oblas s ha ing an impac on angiogenesis,
as well [38].
3.2. Mela onin and Den al Implan s
Missing and de ec i e ee h a e common in humans, especially in middle-aged and elde ly people,
as a consequence o aging. Due o his si ua ion, a highe numbe o implan s a e needed o den al
eposi ion. Imp o ing implan success a e and achie ing a as e osseoin eg a ion a e impo an goals
in den is y. The osseoin eg a ion o implan s is ela ed o he di ec apposi ion o new bone in con ac
wi h he implan su ace [
39
], as well as o he emodelling o he p e-exis ing one. The p oduc ion
o new bone in ol es a cascade o di e en e en s, such as cell ma u a ion and apposi ion, ascula
in asion, and bone o ma ion and mine alisa ion. The ea ly s abili y o implan s is ex emely impo an
o a oid hei ailu e, and he p ocess o in eg a ion may be accele a ed h ough he local deli e y o
g ow h ac o s, as seems o be he case wi h he applica ion o mela onin [2].
The use o mela onin o p omo e bone egene a ion in den al implan placemen was assessed in
se e al s udies, based on di e en animal models in which he au ho s employed mela onin alone o
in combina ion wi h o he subs ances, such as, g ow h ho mone o po cine bone [
2
,
40
–
47
]. The s udies
using mela onin o p omo e den al implan s abili y e alua ed in his e iew a e summa ised in Table 1.
Table 1. Summa y o s udies ocusing on he use o mela onin in den al implan s placemen .
S udy Animal Model Animals/
Implan s Time Alone o
Combina ion Resul s
Cu ando e al.,
2008 [2]Beagle dog 12/72 2 weeks Alone ↑BIC in mela onin g oup
Takechi e al.,
2008 [40]Wis a a 10/20 4 weeks + FGF-2 ↑BIC and bone densi y in
combina ion g oup
Cal o-Gui ado e al.,
2010 [41]Beagle dog 12/48 4 weeks + po cine bone ↑BIC, bone densi y and new
bone in combina ion g oup
Gua dia e al.,
2015 [42]Beagle dog 12/72 5 and 8 weeks Alone ↑Bone o ma ion in
mela onin g oup
Muñoz e al.,
2012 [43]Beagle dog 12/48 2, 5 and
8 weeks
+ G ow h
ho mone
↑BIC ando bone densi y a
2 and 5 weeks in
combina ion g oup
T esgue es e al.,
2012 [44]Rabbi 10/40 4 weeks Alone ↑ abecula BIC in
mela onin g oup
Salomó-Coll e al.,
2015 [45]Foxhound dog 6/24 12 weeks Alone ↑
o al BIC in mela onin g oup
Cal o-Gui ado e al.,
2015 [47]Rabbi 20/80 1 and 10 weeks Alone
↑BIC in i anium and
zi conium implan s a 1 week,
in zi conium a 10 weeks
The his omo phome ic pa ame e s used o e alua e he success o implan in eg a ion in he
di e en s udies we e: bone o implan con ac (BIC, which e e s o he o al leng h o pe cen age
o he implan su ace in con ac wi h bone), bone densi y (BV/TV, which is he a io o bone wi h
espec o he o al olume o he issue), and new bone a ea and in e - h ead bone (which is he bone
inside he h eads o he implan ). In addi ion, se e al s udies epo ed his ological indings, such as
he appea ance o new issue and i s mine alisa ion, he di e en ypes o cells obse ed in he issue
and blood essels o ma ion.
Mos s udies e alua ed in his e iew epo ed ha in a sho pe iod o ime a e he implan
placemen , anging be ween wo and eigh weeks, mela onin signi ican ly inc eased BIC, BV/TV, new
bone a ea, and in e - h ead bone, leading also o an inc ease in he os eoblas p oli e a ion in he
pe i-implan zone [
2
,
42
]. In a s udy using mela onin in combina ion wi h po cine bone in i anium
In . J. Mol. Sci. 2017,18, 865 5 o 13
implan s, his combina ion signi ican ly imp o ed BIC, bone densi y, and new bone a ea in compa ison
wi h he use o po cine bone alone [
41
]. In a s udy conduc ed by Muñoz e al. [
43
] he use o mela onin,
along wi h g ow h ho mone in dogs, p oduced a signi ican imp o emen o all he osseoin eg a ion
pa ame e s a wo and i e weeks; howe e , no s a is ical di e ences we e obse ed when adminis e ed
a eigh weeks, suppo ing he concep ha he use o mela onin is mo e e ec i e du ing he ea ly
s ages o bone healing.
The use o mela onin was also s udied o enhance osseoin eg a ion in immedia e implan s placed
in a dog mandible [
45
], ob aining a signi ican imp o emen o o al BIC and in e - h ead bone
a 12 weeks. These indings ag ee wi h hose ob ained in implan s placed in abbi ibia, whe e
he p esence o well- emodelled co ical bone and new on s o os eoblas s could be obse ed in
animals ea ed wi h mela onin compa ed o he con ol g oup [
44
,
46
], as well as inc eased abecula ,
bu no co ical BIC. The e ec o mela onin in zi conia implan s was s udied by he g oup o
Cal o-Gui ado [47], ob aining be e esul s a one and ou weeks in he ea ed implan s.
Cal o-Gui ado e al. [
48
] s udied he e ec s o he applica ion o mela onin o apigenin on
pos -ex ac ion socke s in dogs. They e alua ed he new bone a ea a 30, 60, and 90 days. The au ho s
ound ha new bone pe cen age a 30 and 60 days was s a is ically signi ican ly inc eased in he
animals ea ed wi h mela onin, concluding ha his molecule seems o s imula e he p oduc ion o a
g ea e numbe o co ical cells and accele a ed conside ably he syn hesis and mine alisa ion o he
os eoid ma ix. In a p e ious s udy, i has been demons a ed ha , in he immedia e pos ope a i e
pe iod ollowing oo h ex ac ion, he e was an inc ease o he oxida i e s ess in he issues, which
can be coun e ac ed by mela onin adminis a ion [49].
The e is ano he s udy on he esponse o bone ing ow h a ound implan s using mela onin and
ib oblas g ow h ac o -2 (FGF-2) in a s, whe e he use o a combina ion o bo h subs ances showed
signi ican esul s in BIC wi h espec o he use o each o hem sepa a ely and wi h he non- ea ed
con ol g oup [40].
A e implan placemen , bone nec osis o en occu s o a ce ain deg ee, and he e is always an
in lamma o y eac ion, as a di ec consequence o su ge y [
50
]. Du ing and a e he su ge y, blood
cells, such as mac ophages and leukocy es, mig a e o he pe i-implan si e and p omo e an inc ease
in ee- adical p oduc ion [
51
,
52
]; mela onin can ac as an i-in lamma o y and an ioxidan and may
a enua e his no mal eac ion o su ge y [
49
,
53
]. The an i-in lamma o y p ope ies o mela onin we e
s udied in compa ison wi h he indome hacin, a nons e oidal an i-in lamma o y d ug, in a a paw
oedema model [
54
], wi h no di e ences being ound; in his s udy, au ho s sugges ed ha mela onin
may ac as a na u al inhibi o o he cyclooxygenase unc ions, modula ing he in lamma o y ac i i y
o his enzyme.
3.3. Mela onin and Pe iodon al Disease
Pe iodon al disease is an in lamma o y diso de cha ac e ised by gingi al bleeding, pe iodon al
pocke o ma ion, and des uc ion o connec i e issue a achmen . This disease s a s in he den al
bio ilm, wi h he s imula ion o he immune esponse agains bac e ia. The mos common o m o
pe iodon al disease in humans is plaque-induced gingi al in lamma ion and may p og ess o mo e
agg essi e o ms o pe iodon i is. In he ad anced o m o he disease, he e is ex eme loss o gingi al
issue and al eola bone.
An impo an aspec in pe iodon al disease is he gene a ion o ee adicals, some o which
we e de i ed om o al bac e ia and o he s o igina ing om he in lamma ion and he induced
immune esponse [55,56]; he ac i a ion o he p o-in lamma o y molecules esul s in he des uc ion
o pe iodon al issues. I has been sugges ed ha an inc ease in bo h oxygen and ni ogen eac i e
species is esponsible o he issue oxida i e damage in pe iodon i is [
57
]. This inc ease in ee
adicals co-exis s wi h a dec ease in he an ioxidan de ence; his imbalance may lead o a subs an ial
de e io a ion o he pe iodon al issues [
58
]. Mela onin plays an impo an ole in he con ol o his
disease due o i s an ioxidan and ee- adical sca enging p ope ies.
In . J. Mol. Sci. 2017,18, 865 6 o 13
The po en ial he apeu ic e ec s o mela onin in pe iodon i is ha e been documen ed
in i o
, as
well as in animal s udies and clinical ials [59].
The ela ionship be ween pe iodon al s a us and he mela onin le el in sali a is s ill
inconclusi e [
60
]. In a s udy measu ing he ela ionship be ween he sali a y mela onin and he deg ee
o pe iodon al disease in humans, Cu ando e al. [
61
] ound ha he e was an in e se co ela ion
be ween hem; as he se e i y o he pe iodon al disease inc eases, he sali a y mela onin le el
dec eases, indica ing ha mela onin may ac as a p o ec o om bac e ial in ec ions. Simila indings
we e epo ed in ano he s udy in which au ho s compa ed he sali a y and he gingi al c e icula
luid le els o mela onin in ou g oups o pa ien s wi h di e en g ades o pe iodon al disease, inding
ha he mo e se e e was he pe iodon i is, he lowe mela onin he le els ound, wi h signi ican
di e ences be ween he heal hy g oup and he wo g oups a ec ed by he disease (ch onic and
agg essi e pe iodon i is) [
62
]. This s udy also epo ed ha he mela onin le els in sali a and gingi al
c e icula luid we e simila (wi h no signi ican di e ences), con i ming he esul s ob ained in
p e ious s udies [
62
]. In he s udy ca ied ou by Gómez-Mo eno [
63
], he au ho s ound ha pa ien s
wi h pe iodon al disease had a signi ican ly lowe plasma and sali a y le el o mela onin, main aining
a simila sali a y/plasma mela onin a io o ha o he heal hy subjec s.
O all he e alua ed s udies on mela onin le els in pa ien s wi h pe iodon al disease, only one,
conduc ed on diabe ic people, ound ha wi h he wo s pe iodon al s a us, he sali a y mela onin
le els we e inc eased [
64
]. The au ho s explained his as a consequence o he o al in lamma o y
media o s. In he emaining s udies, he co ela ion be ween sali a y mela onin le els and pe iodon al
disease was nega i e [61–63].
These low concen a ions o mela onin ound in sali a o pa ien s wi h pe iodon al disease may
be a esul o i s highe use as a ee- adical sca enge and an i-in lamma o y, because o he ele a ed
le el o eac i e oxygen species and in lamma ion ound in hese pa ien s.
In a s udy on liga u e-induced pe iodon i is in a s, he ea men o he animals wi h mela onin
seemed o alle ia e gingi al in lamma ion due o he inhibi ion o he p oduc ion o in lamma o y
cy okines [
65
], and he au ho s concluded ha mela onin could dec ease he oxida i e s ess and
pe iodon al in lamma ion h ough down egula ion o in lamma o y cy okines and es o ing he
concen a ion o an ioxidan s in he issues.
Se e al esea ch s udies suppo he idea ha mela onin could be used as a bioma ke o
moni o ing he se e i y o pe iodon al disease [66,67], as well as a possible ea men s a egy.
3.4. O he E ec s o Mela onin on he O al Ca i y
Mela onin was used o e ical bone augmen a ion in a a cal a ia model [
68
].
Bone augmen a ion is impo an o egene a e bone in localised de ec s, whe e he e is insu icien
olume o den al implan placemen , and he e ical bone augmen a ion is he mos di icul o
achie e, because i means p oducing bone in an a ea whe e i had no exis ed be o e [
69
]. In he
s udy ca ied ou by Shino e al., he new bone egene a ion in a secluded space in a cal a ia was
signi ican ly g ea e in animals ea ed wi h mela onin han in hose wi hou i a 12 weeks, wi h a
signi ican inc ease in he numbe o new blood essels and os eoblas -like cells [68].
Ano he s udied e ec o mela onin e e s o oo h de elopmen . Mela onin has a ole in i by
egula ing cellula p ocesses in odon ogenic cells [
70
]. The ecep o 1a o mela onin was exp essed in
sec e o y ameloblas s, in he cells o he s a um in e medium and s ella e e iculum, in he ex e nal
epi helial cells, in odon oblas s, and in den al sac cells in he oo h ge ms o humans [
71
], sugges ing
ha his subs ance may ha e an e ec on hese s uc u es o oo h de elopmen .
Mela onin has an oncos a ic ac i i y due o i s an i-p oli e a i e ac ion, he s imula ion o
immuni y, and he modula ion o oncogene exp ession; i s an i-in lamma o y, an ioxidan , and
an i-angiogenic p ope ies a e also impo an [
72
]. The an icance ac i i y was p o en
in i o
and
in p elimina y s udies
in i o
[
72
], bu he conc e e mechanism by which mela onin supp esses
cance g ow h is s ill o be comple ely de e mined, se e al mechanisms being p oposed, such as
In . J. Mol. Sci. 2017,18, 865 7 o 13
he ep ession o he hypo halamic-pi ui a y- ep oduc i e axis, enhancemen o immune unc ion,
and di ec an i-p oli e a i e e ec s h ough a ious ecep o s, including mela onin ecep o 1a [
73
].
In addi ion o i s p ope an i-cance ac i i y, mela onin can be use ul in cance pa ien s as a pallia i e
he apy o educe o con ol he side e ec s o chemo he apy, due o i s an i-cachec ic, an i-as hemic,
and h ombopoie ic p ope ies [
74
], as well as i s abili y o p o ec o al issues om ionising adia ion,
limi ing he molecula damage o mi ochond ia and he p esen a ion o o al mucosi is [75].
The e ec s o mela onin in cance we e due o i s abili y o elimina e eac i e oxygen species,
which a e messenge s o cance cell di ision [
72
] and he ampli ica ion o he an i umo ac i i y o
IL-2 [
76
]. Wi h ega d o o al cance , i has been specula ed ha he es o a ion o mela onin ecep o
1a exp ession, in an exogenous way, inhibi s he g ow h o o al squamous cell ca cinoma [77].
Finally, mela onin could be used in he o al ca i y as a ea men o bac e ial and i al in ec ions.
The bene icial e ec s o mela onin as an an i i al was s udied in se e al ypes o in ec ions (Venezuelan
equine encephalomyeli is, Wes Nile encephali is, e c.), whe e he use o mela onin as a ea men had
bene icial e ec s in diminishing he i emia and he consequen mo ali y [
78
]. Rega ding he diseases
o he o al ca i y, mela onin was s udied in he pes i us ea men and was compa ed wi h he e ec
o acyclo i (a common ea men used o his disease) [
79
]. The esul s showed ha he e icacy o
mela onin in diminishing he se e i y o he in ec ion was almos as e ec i e as he an i i al d ug,
wi h he bene i o ha ing ewe side e ec s. The bene i o mela onin in i al in ec ions seems o be
due o he immunomodula o y ac ion in he s imula ion o IL-1
β
, which has an i i al e ec s, as well as
an i-oxida i e and an i-in lamma o y e ec s. Ano he ole o mela onin in i al in ec ions could be
ha o imp o ing an immune sys em weakened by ee adicals [80].
In bac e ial in ec ions, mela onin was used as a success ul he apy in se e al
in i o
models [
81
,
82
], wi h ac ion agains G am-posi i e and G am-nega i e mic oo ganisms, bu wi h a highe e icacy
on he la e ; i also showed e icacy agains di e en s ains o an ibio ic- esis an bac e ia [
83
].
The possible mechanism o ac ion o mela onin as an an ibio ic included he egula ion o he
p oli e a ion/duplica ion o bac e ia, he educ ion o lipid up ake [
83
], and high me al binding
capaci y, including i on [
84
]. In he o al ca i y, he an ibac e ial ac i i y o mela onin could be use ul in
con olling pe iodon al disease and in den al ca ies induc ion [85].
4. Discussion
A pha macological doses, mela onin caused he inhibi ion o bone eso p ion and an inc ease
in bone mass, accele a ing he mine alisa ion p ocess o he bone ma ix [
28
]. This could explain he
g ea e olume o mine alised bone, as well as new bone o ma ion a ound he implan s ea ed wi h
mela onin, as seen in all o he s udies e alua ed.
The use o mela onin in implan s enhances an ea lie osseoin eg a ion in di e en animal
models [
2
,
40
–
47
]. Mela onin p oduces highe alues o BIC and in e - h ead bone, which is based
on he di ec ac ion o his molecule on he os eoblas s, wi h a highe a e o ma u a ion and o bone
ma ix p oduc ion and mine alisa ion [45].
Mela onin appea s o ha e a posi i e e ec in he osseoin eg a ion o den al implan s du ing he
ea ly s ages o healing and could be used as a biomime ic agen du ing he implan su ge y [
2
,
86
],
making he healing p ocess mo e e ec i e, enhancing he ini ial condi ions o he ecep o issues,
educing he ime o osseoin eg a ion, and imp o ing he pa ien ’s quali y o li e. In mos o he
e alua ed s udies, he e ec o mela onin was enhanced in he ea ly phase a e he implan placemen ,
anging om wo o eigh weeks, and he e idence o he mela onin bene i s a e less e iden a la e
s ages o he healing p ocess [
2
,
41
–
44
]. I was obse ed ha he ci cula ing hal -li e o mela onin is
app oxima ely 23 min [
87
], hus, some au ho s specula e on he po en ial use o ca ie s in mela onin
ea men in o de o elease i g adually and inc ease he hal -li e in he issues, he inc ease o he
mela onin e ec du ing implan placemen being pa icula ly in e es ing [43].
Pe iodon al diseases a e he esul o he e ec s o bac e ia and hei p oduc s on he hos esponse
and i has been sugges ed ha he e a e biological media o s, such as mela onin, which can con ibu e
In . J. Mol. Sci. 2017,18, 865 8 o 13
o he p o ec ion o pe iodon al issues [
88
]. When su e ing om pe iodon al disease, he amoun
o mela onin in sali a and in gingi al c e icula luid seems o be lowe when he pa hology is mo e
se e e, indica ing ha i may play a p o ec i e ole agains his disease, al hough u he esea ch is
equi ed o con i m his hypo hesis. The p o ec i e ole o mela onin on pe iodon al issues migh
be explained o some ex en by i s an imic obial ac ion [
60
], i s ac i a ion o he immune sys em [
89
],
and i s an i-in lamma o y and ee adical sca enge e ec [
90
]. In addi ion, mela onin may modula e
pe iodon al des uc ion by inhibi ing p os aglandin E
2
syn hesis and, he e o e, inhibi os eoclas
di e en ia ion [
91
], neu alising eac i e oxygen species a he le el o os eoclas lacuna, wi h he
inhibi ion o bone eso p ion and s imula ing os eoblas di e en ia ion [30,63].
In cance ea men , mela onin is used as a possible he apeu ic a ge , wi h consis en e ec s
agains solid umou s, as well as a pallia i e he apy o educe o con ol he side e ec s o
chemo he apy. The di e en obse a ions sugges ha he use o mela onin should be conside ed in
clinical ials, adminis e ed as a single ea men o in combina ion wi h o he an icance d ugs [92].
5. Conclusions
In conclusion, he po en ial use o mela onin in o al diseases, such as implan placemen o
pe iodon i is, was s udied by se e al g oups, mos o hem wi h a ou able esul s. Cu en ly, he e is
no consensus o he bes ou e o adminis a ion o his molecule, as well as in e ms o he dosage
needed o a good e ec ; hus, u he esea ch should be ca ied ou in his sense. Howe e , he
ela ionship be ween mela onin le els in sali a and c e icula luid and pe iodon al disease is no
comple ely unde s ood, and u he s udies should be conduc ed since he esul s we e di e en
depending on he e alua ed s udy. Finally, clinical s udies should also be pe o med, o obse e he
e ec s o mela onin on implan placemen s in humans.
Acknowledgmen s:
In memo y o An onio Cu ando So iano, Uni e si y o G anada. Cu ando was an en husias ic
de ende o he use o mela onin in den is y.
Au ho Con ibu ions:
Ma ia Pe muy, Mónica López-Peña, An onio González-Can alapied a and Fe nando Muñoz
con ibu ed equally o he e iew o he li e a u e o he manusc ip . In addi ion, Ma ía Pe muy d a ed he
manusc ip , Mónica López-Peña and Fe nando Muñoz ead and c i ically e ised he manusc ip . All au ho s ga e
inal app o al and ag ee o be accoun able o all aspec s o he wo k.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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