*Co esponding au ho : Jiuzhou Lin
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion Liscense 4.0.
The e ec s and mechanisms o si eles a in alle ia ing pos - esusci a ion b ain inju y
Yaling Jin 1, 2, Min Tang 2, Lihui Chen 2, Wei ing Chen 2 and Jiuzhou Lin 2, *
1 Zhejiang Chinese Medical Uni e si y, Hangzhou, Zhejiang 310053 China.
2 Depa men o Eme gency Medicine, The Fi s People's Hospi al o Linhai, Taizhou, Zhejiang 317000 China.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 21(01), 180-185
Publica ion his o y: Recei ed on 23 No embe 2024; e ised on 06 Janua y 2025; accep ed on 08 Janua y 2025
A icle DOI: h ps://doi.o g/10.30574/wjbphs.2025.21.1.1109
Abs ac
Objec i e: To in es iga e he neu op o ec i e e ec s o si eles a (SV) in a po cine ca diac a es - esusci a ion model
while explo ing i s associa ion wi h he NF-κB/NLRP3 pa hway.
Me hods: Fi een heal hy male pigs we e andomly assigned o he sham ope a ion g oup (Sham, n=5), he
ca diopulmona y esusci a ion g oup (CPR, n=5), and he CPR wi h SV ea men g oup (CPR+SV, n=5). Ca diac a es
was induced by en icula ib illa ion o 9 minu es in he CPR and CPR+SV g oups, ollowed by 6 minu es o
ca diopulmona y esusci a ion o es ablish he expe imen al model. To assess he po en ial p o ec i e e ec s o SV, i e
minu es a e success ul esusci a ion, he CPR+SV g oup ecei ed SV a 10 mg/kg ia emo al ein in usion o 1 hou
using a mic o-in usion pump. Blood samples we e collec ed om he emo al ein a baseline and a 0.5, 1, 2, and 4
hou s pos - esusci a ion o se um le els o neu on-speci ic enolase (NSE) and S100β p o ein, ecognized as ma ke s
o b ain inju y, ia ELISA. Neu ological unc ion was assessed 24 hou s pos - esusci a ion using neu ological de ici
sco es (NDS). The animals we e eu hanized 24 hou s pos - esusci a ion, and le en icula apical myoca dial and
on al lobe co ex issues we e ha es ed. B ain issue le els o in lamma o y ma ke s, IL-1β and IL-18, we e analyzed
using Wes e n blo ing. Wes e n blo was used o e alua e he e ec o SV in educing he exp ession le els o NF-κB,
NLRP3, clea ed caspase-1, and GSDMD, key ma ke s o py op osis, in he b ain issues o pigs a e CPR.
Resul s: Pos - esusci a ion, he CPR and CPR+SV g oups exhibi ed signi ican ly highe se um le els o NSE and S100β
and ele a ed NDS sco es compa ed o he Sham g oup (all P<0.05). Ne e heless, he CPR+SV g oup showed
signi ican ly imp o ed neu ological sco es and educed le els o b ain inju y ma ke s a all ime poin s pos -
esusci a ion e sus he CPR g oup (P<0.05). A 24 hou s pos - esusci a ion, IL-1β and IL-18 le els in he b ain issues
o CPR and CPR+SV g oups we e ma kedly highe han hose in he Sham g oup (P<0.05). Con e sely, he le els o
in lamma o y ac o s in he CPR+SV g oup we e signi ican ly educed compa ed o he CPR g oup (P<0.05). A 24 hou s
pos - esusci a ion, b ain issue exp ession o NF-κB, NLRP3, clea ed caspase-1, and GSDMD was ma kedly ele a ed in
he CPR g oup (P<0.05). SV ma kedly supp essed he exp ession o hese py op osis-associa ed p o eins (P<0.05),
highligh ing i s po en ial ole in neu op o ec i e ia inhibi ion o he NF-κB/NLRP3 pa hway.
Conclusion: SV e ec i ely mi iga es pos - esusci a ion b ain inju y and enhances neu ological ou comes, likely h ough
i s egula o y e ec s on he NF-κB/NLRP3 pa hway.
Keywo ds: Ca diac A es ; Ca diopulmona y Resusci a ion; B ain Inju y; Si eles a Sodium; NF-κB/NLRP3
1. In oduc ion
Ca diac a es is a equen ly encoun e ed c i ical condi ion in clinical se ings, wi h a global incidence a e o 1 pe
1,000 annually (0.1%), making i he hi d leading cause o dea h a e cance and ca dio ascula diseases[1, 2]. Despi e
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 21(01), 180-185
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ad ancemen s in mode n medicine and he widesp ead adop ion o ca diopulmona y esusci a ion (CPR) echniques,
he a e o e u n o spon aneous ci cula ion (ROSC) anges om 30% o 48%, bu only abou 10% o pa ien s achie e
no mal unc ional eco e y. Addi ionally, nea ly 70% o pa ien s succumb o ischemic b ain inju y o expe ience long-
e m neu ological de ici s[3, 4]. Thus, he se e i y o pos - esusci a ion b ain inju y is a key indica o o he success o
ca diac a es ea men [5]. This unde sco es he u gen need o e ec i e in e en ions ha can mi iga e hese
de as a ing ou comes.
S udies ha e shown ha py op osis, a no el o m o in lamma o y cell dea h, exace ba es a ge o gan damage h ough
plasma memb ane up u e and he elease o in acellula oxins and in lamma o y media o s. Impo an ly, py op osis
also plays a signi ican ole in he p og ession o pos -ca diac a es b ain inju y[6, 7]. Resea ch has demons a ed ha
NOD-like ecep o py in domain 3 (NLRP3) ac s as a key ups eam p o ein in ini ia ing py op osis, while nuclea ac o -
κB (NF-κB) se es as a c i ical ups eam egula o o NLRP3 ac i i y[8, 9]. In his con ex , a ge ing he NF-κB/NLRP3-
media ed py op osis pa hway could o e no el he apeu ic a ge s o mi iga ing pos - esusci a ion b ain inju y.
Addi ionally, si eles a (SV), a speci ic inhibi o o neu ophil elas ase, exe s mul iple biological e ec s ha a e
p ima ily a ibu ed o i s an i-in lamma o y p ope ies. I has shown e icacy in alle ia ing b ain inju y ollowing local
ischemia- epe usion[10, 11], ye i s speci ic e ec s on global ce eb al ischemia- epe usion inju y and he unde lying
mechanisms in ol ing he NF-κB/NLRP3 pa hway emain unclea .
This s udy aims o alida e he he apeu ic e ec s o SV on pos - esusci a ion b ain inju y in a po cine model and o
explo e i s po en ial mechanism o inhibi ing py op osis ia he NF-κB/NLRP3 pa hway, p o iding new insigh s in o
ea men s a egies.
2. Ma e ials and Me hods
2.1. Expe imen al Animal Sou ces and G ouping In e en ions
A o al o 15 heal hy male domes ic pigs (32-40 kg) we e supplied by Shanghai Jiagan Bio echnology Co., L d. (Animal
Ce i ica e No. SCXK (Shanghai) 2020-0006). The animals we e andomly alloca ed o he Sham g oup, he CPR g oup,
and he CPR+SV g oup. The Sham g oup unde wen su gical p epa a ion wi hou en icula ib illa ion induc ion o
esusci a ion, se ing as a con ol g oup. In bo h he CPR and CPR+SV g oups, ca diac a es was induced by en icula
ib illa ion. The CPR+SV g oup ecei ed an in usion o SV a 10 mg/kg h ough he emo al ein, ini ia ed 5 minu es a e
success ul esusci a ion and con inued o 1 hou .
A e a 12-hou as , anes hesia was induced ia in amuscula injec ion o ile amine/zolazepam (5 mg/kg) and
xylazine (1 mg/kg) in o he glu eal muscles. Following ini ial anes hesia, he animals we e placed on a iangula
su gical boa d connec ed o an ECG and oxygen sa u a ion moni o s, and in a enously anes he ized wi h p opo ol (2
mg/kg) h ough an au icula ein cannula, ollowed by main enance in usion a 4-6 mg/kg/h. Endo acheal in uba ion
was pe o med using a e e ina y la yngoscope, ollowed by mechanical en ila ion wi h olume-con olled mode, se
o idal olume 8-10 mL/kg, espi a o y a e 12 b ea hs/min, and oxygen concen a ion 21%. Su gical incisions we e
made o ca he e inse ion in he igh emo al a e y and ein o moni o blood p essu e, a ial p essu e, and o blood
sampling, d ug deli e y, and en icula ib illa ion induc ion by inse ing an elec ode in o he igh ex e nal jugula
ein h ough a su gical incision.
A e s abiliza ion, 1 mA al e na ing cu en was deli e ed ia he elec ode o induce en icula ib illa ion. Ca diac
a es was con i med by he appea ance o en icula ib illa ion wa es on he ECG and a d op in blood p essu e o a
la line. The en ila o was immedia ely disconnec ed, and he animals we e obse ed wi hou in e en ion o 9
minu es. CPR was pe o med ollowing in e na ional guidelines. Two p o essional escue s al e na ed ches
comp essions, moni o ed by a eedback de ice o ensu e a dep h o 5-6 cm and a equency o 100-120
comp essions/min. Manual comp essions and bag- al e en ila ion we e main ained a a 30:2 a io. Epineph ine (20
µg/kg) was injec ed in a enously s a ing 2 minu es a e ini ia ing CPR, wi h he same dose epea ed e e y 3 minu es
he ea e . A e 6 minu es o CPR, de ib illa ion was pe o med using a biphasic shock a 150 J. Res o a ion o
sup a en icula hy hm and main enance o mean a e ial p essu e abo e 50 mmHg we e e alua ed immedia ely. I
spon aneous hy hm and blood p essu e we e no es o ed, CPR was esumed o 2 minu es ollowed by de ib illa ion,
epea ed up o 5 cycles. Resusci a ed animals we e econnec ed o mechanical en ila ion and obse ed unde
con inuous anes hesia moni o ing o 6 hou s. A e his pe iod, mechanical en ila ion was discon inued, and he
endo acheal ube and ascula ca he e s we e ca e ully emo ed. The su gical incisions we e disin ec ed and su u ed,
and he animals we e e u ned o he pen o 24 hou s o u he obse a ion.
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2.2. Expe imen al Obse a ion Indica o s
Neu ological unc ion e alua ion: The animals' neu ological s a us was assessed a baseline and 24 hou s pos -modeling
using he NDS, which e alua es se en pa ame e s: espi a o y s a us, consciousness, s anding/walking/mo o abili y,
muscle one, and es ain esponses. The sco ing sys em anges om 0 o 400, wi h highe sco es indica ing mo e
se e e neu ological impai men .
• De ec ion o B ain Inju y Bioma ke s: Venous blood was d awn a baseline and 1, 2, 4, and 24 hou s pos -
modeling, cen i uged o ob ain se um, and s o ed a -80°C. Se um le els o NSE and S100β, indica i e o b ain
inju y, we e subsequen ly measu ed by enzyme-linked immunoso ben assay (ELISA).
• De ec ion o NF-κB/NLRP3 Signaling in B ain Tissue: A 24 hou s pos -modeling, he animals we e
eu hanized, and he ce eb al co ex was apidly excised, chopped in o small pieces, and ozen in liquid
ni ogen. P o ein exp ession le els o NF-κB and NLRP3 signaling molecules we e hen analyzed by Wes e n
blo ing.
• De ec ion o Key Py op o ic P o eins and P oduc s in B ain Tissue: A 24 hou s pos -modeling, he animals
we e eu hanized, and he ce eb al co ex was excised and immedia ely ozen. Wes e n blo ing was used o
quan i y p o ein le els o clea ed caspase-1 and he N- e minal domain o GSDMD, as well as he issue
concen a ions o IL-1β and IL-18.
2.3. S a is ical Analysis Me hods
Da a analysis was pe o med wi h SPSS 22.0 s a is ical so wa e (IBM, USA). The no mali y o he dis ibu ion o
measu emen da a was i s es ed. Once con i med o ollow a no mal dis ibu ion, da a we e exp essed as mean ±
s anda d de ia ion (x±s). A one-way analysis o a iance (ANOVA) was used o compa isons among h ee g oups, and
pai wise compa isons we e conduc ed using Bon e oni pos hoc es s. Fo ca ego ical da a, esul s we e exp essed as
pe cen ages. Compa isons be ween wo g oups we e pe o med using Fishe 's exac es when app op ia e. A P- alue
o <0.05 was conside ed s a is ically signi ican .
3. Resul
3.1. Neu ological Func ion and B ain Inju y Ma ke s
A e esusci a ion, he se um concen a ions o NSE and S100β we e signi ican ly highe in he CPR and CPR+SV g oups
compa ed o he Sham g oup, wi h an inc ease in NDS sco es (all P<0.05). In con as , he neu ological unc ion sco es
and b ain inju y bioma ke le els in he CPR+SV g oup we e signi ican ly lowe a all ime poin s pos - esusci a ion
compa ed o he CPR g oup (P<0.05), indica ing ha SV has a p o ec i e e ec agains b ain inju y a e esusci a ion.
Figu e 1 Compa ison o neu ological unc ion and b ain inju y bioma ke s in expe imen al pigs ac oss g oups.
*P<0.05 compa ed o Sham g oup; *#P<0.05 compa ed o CPR g oup
3.2. In lamma o y Cy okine Le els
A e 24 hou s o esusci a ion, he le els o IL-1β and IL-18 in he b ain issue o animals in he CPR and CPR+SV g oups
we e signi ican ly highe han hose in he Sham g oup (P<0.05). Howe e , he le els o in lamma o y ac o s in he
CPR+SV g oup we e signi ican ly lowe han in he CPR g oup (P<0.05), indica ing ha SV can alle ia e b ain issue
in lamma ion.
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Figu e 2 Compa ison o b ain issue in lamma o y esponse damage in expe imen al pigs pos - esusci a ion. *P<0.05
compa ed o Sham g oup; *#P<0.05 compa ed o CPR g oup
3.3. Regula ion o py op osis pa hway
A e 24 hou s o esusci a ion, he exp ession o NF-κB, NLRP3, Clea ed Caspase-1, and GSDMD in he b ain issue o
he CPR g oup was signi ican ly ele a ed (P<0.05). Howe e , SV signi ican ly inhibi ed he exp ession o hese
py op osis- ela ed p o eins (P<0.05), sugges ing ha SV exe s neu op o ec i e e ec s by inhibi ing he NF-κB/NLRP3
pa hway.
Figu e 3 E ec o SV on he NF-κB/NLRP3 py op osis signaling pa hway in b ain issue pos - esusci a ion. *P<0.05
compa ed o Sham g oup; *#P<0.05 compa ed o CPR g oup
4. Discussion
This s udy success ully es ablished a la ge animal pig CPR model and used i o p elimina ily in es iga e he p o ec i e
e ec o SV in educing b ain inju y a e esusci a ion. The esul s showed ha , compa ed o he CPR g oup, SV
ea men signi ican ly educed b ain dys unc ion and b ain inju y ma ke s le els in expe imen al pigs pos -
esusci a ion. Fu he analysis sugges s ha i s p o ec i e e ec may be ela ed o he inhibi ion o b ain issue
in lamma ion and he egula ion o he NF-κB/NLRP3 py op osis signaling pa hway.
SV, a speci ic neu ophil elas ase inhibi o ha alle ia es a ge o gan damage by inhibi ing he in lamma o y esponse
media ed by his enzyme. I has been shown o ha e a ious o gan-p o ec i e e ec s, including an i-in lamma o y,
an ioxidan , and an i-apop o ic p ope ies[12]. In he con ex o ischemia- epe usion inju y, s udies ha e shown ha
SV e ec i ely alle ia es local ischemia- epe usion damage in mul iple o gans, showing signi ican he apeu ic
po en ial. Aune e al[13] demons a ed in an ex i o a hea ischemia- epe usion inju y model ha SV educed
myoca dial in a c ion a ea and imp o ed le en icula con ac ion unc ion. I s p o ec i e mechanism may be ela ed
o educing he p oduc ion o eac i e oxygen species and main aining ni ic oxide le els. In sys emic ischemia-
epe usion e en s, exis ing s udies ha e only epo ed ha SV mi iga es hemo hagic shock-induced lung inju y by
inhibi ing he NF-κB-media ed in lamma o y esponse pa hway.
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B ain inju y bioma ke s (NSE and S100β) a e c ucial indica o s ha e lec he ex en o neu onal damage, and hei
ele a ed le els a e o en associa ed wi h se e e neu ological dys unc ion. This s udy aims o explo e he po en ial
p o ec i e e ec o SV in alle ia ing b ain inju y ollowing esusci a ion. Acco ding o ele an li e a u e, SV was
adminis e ed a a dose o 10 mg/kg, 5 minu es a e success ul esusci a ion[13, 14]. The esul s showed ha bo h he
neu o unc ional sco es (NDS) and se um concen a ions o b ain inju y ma ke s (NSE and S100β) in he CPR and
CPR+SV g oups we e signi ican ly highe han hose in he Sham g oup, demons a ing signi ican b ain dys unc ion
and inju y pos - esusci a ion. Howe e , a e SV ea men , he neu o unc ional indica o s in he CPR+SV g oup
imp o ed o e all, while he concen a ions o b ain inju y ma ke s dec eased signi ican ly a speci ic ime poin s.
Ikegame e al[10] ound in a mouse ocal ce eb al ischemia model ha SV signi ican ly educed b ain edema and
capilla y leakage, he eby imp o ing neu ological unc ion a e ce eb al ischemia. This sugges s ha SV may exhibi a
neu op o ec i e e ec by alle ia ing neu ological dys unc ion and b ain inju y a e esusci a ion.
In lamma ion is a pi o al mechanism o b ain inju y ollowing esusci a ion. The subs an ial ise in p o-in lamma o y
ac o s such as IL-1β and IL-18 is a majo con ibu o o he exace ba ion o b ain inju y. This s udy demons a ed ha
ea men wi h SV ma kedly dec eased he le els o hese in lamma o y ma ke s, likely due o he inhibi ion o he NF-
κB signaling pa hway and he subsequen supp ession o NLRP3 ac i i y. This mechanism has also been con i med in
s udies o ischemia- epe usion inju y in o he o gans. Fo ins ance, Hu e al[15] obse ed in a mouse model o li e
ischemia- epe usion and in pa ien s unde going li e esec ion, ha SV signi ican ly mi iga ed li e ischemia-
epe usion inju y by inhibi ing he Ninj1/Dusp1 axis, he eby cu ailing in lamma o y signaling and enabling apid
eco e y o li e unc ion a e su ge y. These indings ein o ce he c i ical ole o he NF-κB/NLRP3 pa hway in b ain
inju y pos - esusci a ion and highligh he po en ial o SV as a he apeu ic agen o managing in lamma ion.
This s udy con i ms ha SV e ec i ely mi iga es b ain inju y a e esusci a ion by educing he exp ession o NLRP3,
clea ed caspase-1, and GSDMD. This inding aligns wi h he c i ical ole o py op osis in b ain inju y as obse ed by Diao
e al in hei esea ch on ca diopulmona y esusci a ion, u he alida ing ha py op osis is a c i ical he apeu ic a ge
o pos - esusci a ion b ain inju y. The inno a ion o his s udy lies in demons a ing SV's ole in egula ing he
py op osis pa hway, he eby opening new a enues o ea ing b ain inju y a e esusci a ion[6].
This s udy has some limi a ions. Sho obse a ion ime: This s udy ocused solely on acu e b ain inju y and
in lamma o y esponses wi hin 24 hou s pos - esusci a ion and did no e alua e long- e m neu ological eco e y and
ch onic in lamma o y changes. Fu u e esea ch should ex end he obse a ion pe iod o assess he ole o SV in long-
e m neu op o ec ion. Mechanism di e si y: While his s udy concen a ed on he NF-κB/NLRP3 pa hway, SV may also
con e p o ec i e e ec s h ough o he mechanisms, such as an ioxida i e s ess and enhancemen o ascula unc ion.
These po en ial mechanisms wa an u he explo a ion ia mul i-omics analysis and cellula -le el expe imen s. Dose
and adminis a ion s a egy: This s udy employed a single dose (10 mg/kg) o SV wi hou examining he dose- esponse
ela ionship o op imal iming o adminis a ion. Fu u e esea ch should sys ema ically explo e he impac o di e en
doses and adminis a ion ou es on he p o ec i e e ec s o SV.
5. Conclusion
In conclusion, SV signi ican ly educes b ain inju y and imp o es neu ological unc ion pos - esusci a ion. I s e icacy
likely due o he inhibi ion o he NF-κB/NLRP3 pa hway. This s udy ad ances ou unde s anding o b ain inju y
ea men ollowing esusci a ion and highligh s he po en ial clinical applica ion o a ge ing his pa hway.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
The au ho s decla e ha hey ha e no compe ing in e es s.
S a emen o e hical app o al
The wo k was complied wi h he Decla a ion o Helsinki and was app o ed by he Ins i u ional Animal Ca e and Use
Commi ee (ZJCLA-20010639).
Au ho Con ibu ions
• Jiuzhou Lin: Resea ch Design, Expe imen al Ope a ion, Thesis W i ing and edi ing;
• Min Tang, Yaling Jin, Wei ing Chen: Expe imen al ope a ion;
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 21(01), 180-185
185
• Lihui Chen, Jiuzhou Lin: Da a collec ion and o ganiza ion, s a is ical analysis
Funding
This wo k was suppo ed by he Zhejiang P o incial Medical Science Founda ion (2023KY410).
A ailabili y o da a and ma e ials
The da ase s used and/o analyzed du ing he p esen s udy a e a ailable om he co esponding au ho upon
easonable eques .
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