Morphine pretreatment protects against cerebral ischemic injury via a cPKCγ‑mediated anti‑apoptosis pathway

Zhao,Xiao-Yan; Li,Jun-Fa; Li,Tian-Zuo; Pan,Chu-Xiong; Xue,Fu-Shan; Wang,Gu-Yan

doi:10.3892/etm.2021.10448

Morphine pretreatment protects against cerebral ischemic injury via a cPKCγ‑mediated anti‑apoptosis pathway

Authors:
- Xiao-Yan Zhao
- Jun-Fa Li
- Tian-Zuo Li
- Chu-Xiong Pan
- Fu-Shan Xue
- Gu-Yan Wang
View Affiliations

Affiliations: Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China, Department of Neurobiology, Capital Medical University; Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, P.R. China, Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China, Department of Anesthesiology, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, P.R. China, Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
Published online on: July 15, 2021 https://doi.org/10.3892/etm.2021.10448
Article Number: 1016

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

It has been reported that morphine pretreatment (MP) can exert neuroprotective effects, and that protein kinase C (PKC) participates in the initiation and development of ischemic/hypoxic preconditioning in the brain. However, it remains unknown whether PKC is involved in MP‑induced neuroprotection. The aim of the present study, which included in vivo and in vitro experiments, was to determine whether the conventional γ isoform of PKC (cPKCγ) was involved in the protective effects of MP against cerebral ischemic injury. The present study included an in vivo experiment using a mouse model of middle cerebral artery occlusion and an in vitro experiment using neuroblastoma N2a cells with oxygen‑glucose deprivation (OGD). Furthermore, a cPKCγ antagonist, Go6983, was used to determine the involvement of cPKCγ in the protective effects of MP against cerebral ischemic injury. In the in vivo experiment, neurological deficits, ischemic infarct volume, neural cell damage, apoptosis and caspase‑3 activation were evaluated. In the in vitro experiment, flow cytometry was used to determine the activation of caspase‑3 in N2a cells with OGD. It was found that MP protected against cerebral ischemic injury. However, intracerebroventricular injection of the cPKCγ antagonist before MP attenuated the neuroprotective effect of MP and increased the activation of cleaved caspase‑3. These findings suggested that MP may provide protection against cerebral ischemic injury via a cPKCγ‑mediated anti‑apoptosis pathway.

View Figures

View References

1	Dabrowska S, Andrzejewska A, Lukomska B and Janowski M: Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation. 16(178)2019.PubMed/NCBI View Article : Google Scholar
2	Mergenthaler P, Dirnagl U and Meisel A: Pathophysiology of stroke: Lessons from animal models. Metab Brain Dis. 19:151–167. 2004.PubMed/NCBI View Article : Google Scholar
3	Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M and van Melle G: Do transient ischemic attacks have a neuroprotective effect? Neurology. 54:2089–2094. 2000.PubMed/NCBI View Article : Google Scholar
4	de Lau LM, den Hertog HM, van den Herik EG and Koudstaal PJ: Predicting and preventing stroke after transient ischemic attack. Expert Rev Neurother. 9:1159–1170. 2009.PubMed/NCBI View Article : Google Scholar
5	Rancurel G: Transient ischemic attacks in the elderly: New definition and diagnostic difficulties. Psychol Neuropsychiatr Vieil. 3:17–26. 2005.PubMed/NCBI(In French).
6	Archer DP, Walker AM, McCann SK, Moser JJ and Appireddy RM: Anesthetic neuroprotection in experimental stroke in rodents: A systematic review and meta-analysis. Anesthesiology. 126:653–665. 2017.PubMed/NCBI View Article : Google Scholar
7	Zhang J, Haddad GG and Xia Y: delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury. Brain Res. 885:143–153. 2000.PubMed/NCBI View Article : Google Scholar
8	Zhang J, Gibney GT, Zhao P and Xia Y: Neuroprotective role of delta-opioid receptors in cortical neurons. Am J Physiol Cell Physiol. 282:C1225–C1234. 2002.PubMed/NCBI View Article : Google Scholar
9	Endoh H, Taga K, Yamakura T, Sato K, Watanabe I, Fukuda S and Shimoji K: Effects of naloxone and morphine on acute hypoxic survival in mice. Crit Care Med. 27:1929–1933. 1999.PubMed/NCBI View Article : Google Scholar
10	Endoh H, Honda T, Ohashi S and Shimoji K: Naloxone improves arterial blood pressure and hypoxic ventilatory depression, but not survival, of rats during acute hypoxia. Crit Care Med. 29:623–627. 2001.PubMed/NCBI View Article : Google Scholar
11	Peart JN, Gross ER and Gross GJ: Opioid-induced preconditioning: Recent advances and future perspectives. Vascul Pharmacol. 42:211–218. 2005.PubMed/NCBI View Article : Google Scholar
12	Mellor H and Parker PJ: The extended protein kinase C superfamily. Biochem J. 332:281–292. 1998.PubMed/NCBI View Article : Google Scholar
13	Kaleli HN, Ozer E, Kaya VO and Kutlu O: Protein kinase C isozymes and autophagy during neurodegenerative disease progression. Cells. 9(553)2020.PubMed/NCBI View Article : Google Scholar
14	Bright R and Mochly-Rosen D: The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke. 36:2781–2790. 2005.PubMed/NCBI View Article : Google Scholar
15	Perez-Pinzon MA, Dave KR and Raval AP: Role of reactive oxygen species and protein kinase C in ischemic tolerance in the brain. Antioxid Redox Signal. 7:1150–1157. 2005.PubMed/NCBI View Article : Google Scholar
16	Kurkinen K, Busto R, Goldsteins G, Koistinaho J and Pérez-Pinzón MA: Isoform-specific membrane translocation of protein kinase C after ischemic preconditioning. Neurochem Res. 26:1139–1144. 2001.PubMed/NCBI View Article : Google Scholar
17	Niu C, Li J, Cui X, Han S, Zu P, Li H and Xu Q: Changes in cPKC isoform-specific membrane translocation and protein expression in the brain of hypoxic preconditioned mice. Neurosci Lett. 384:1–6. 2005.PubMed/NCBI View Article : Google Scholar
18	Sun MK, Hongpaisan J, Nelson TJ and Alkon DL: Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains. Proc Natl Acad Sci USA. 105:13620–13625. 2008.PubMed/NCBI View Article : Google Scholar
19	Voronkov AV and Mamleev AV: Endothelial dysfunction and Protein kinase C activity development interrelation at ischemic injury of a brain. Patol Fiziol Eksp Ter. 60:134–142. 2016.PubMed/NCBI
20	Zhang N, Yin Y, Han S, Jiang J, Yang W, Bu X and Li J: Hypoxic preconditioning induced neuroprotection against cerebral ischemic injuries and its cPKCγ-mediated molecular mechanism. Neurochem Int. 58:684–692. 2011.PubMed/NCBI View Article : Google Scholar
21	Wolf R, Koch T, Schulz S, Klutzny M, Schröder H, Raulf E, Bühling F and Höllt V: Replacement of threonine 394 by alanine facilitates internalization and resensitization of the rat mu opioid receptor. Mol Pharmacol. 55:263–268. 1999.PubMed/NCBI View Article : Google Scholar
22	Mann A, Illing S, Miess E and Schulz S: Different mechanisms of homologous and heterologous μ-opioid receptor phosphorylation. Br J Pharmacol. 172:311–316. 2015.PubMed/NCBI View Article : Google Scholar
23	Vanderschuren LJ, De Vries TJ, Wardeh G, Hogenboom FA and Schoffelmeer AN: A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats. Eur J Neurosci. 14:1533–1538. 2001.PubMed/NCBI View Article : Google Scholar
24	Ferguson SM, Thomas MJ and Robinson TE: Morphine-induced c-fos mRNA expression in striatofugal circuits: Modulation by dose, environmental context, and drug history. Neuropsychopharmacology. 29:1664–1674. 2004.PubMed/NCBI View Article : Google Scholar
25	Cunningham CL, Bakner L, Schuette LM and Young EA: Morphine and ethanol pretreatment effects on expression and extinction of ethanol-induced conditioned place preference and aversion in mice. Psychopharmacology (Berl). 238:55–66. 2021.PubMed/NCBI View Article : Google Scholar
26	Blanchard OL and Smoliga JM: Translating dosages from animal models to human clinical trials--revisiting body surface area scaling. FASEB J. 29:1629–1634. 2015.PubMed/NCBI View Article : Google Scholar
27	Sacchetti B and Bielavska E: Chelerythrine, a specific PKC inhibitor, blocks acquisition but not consolidation and retrieval of conditioned taste aversion in rat. Brain Res. 799:84–90. 1998.PubMed/NCBI View Article : Google Scholar
28	Gschwendt M, Dieterich S, Rennecke J, Kittstein W, Mueller HJ and Johannes FJ: . Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 392:77–80. 1996.PubMed/NCBI View Article : Google Scholar
29	Muñoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J and Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke. 34:164–170. 2003.PubMed/NCBI View Article : Google Scholar
30	Rabinstein AA: Update on treatment of acute ischemic stroke. Continuum (Minneap Minn). 26:268–286. 2020.PubMed/NCBI View Article : Google Scholar
31	Rodriguez R, Santiago-Mejia J, Gomez C and San-Juan ER: A simplified procedure for the quantitative measurement of neurological deficits after forebrain ischemia in mice. J Neurosci Methods. 147:22–28. 2005.PubMed/NCBI View Article : Google Scholar
32	Wexler EJ, Peters EE, Gonzales A, Gonzales ML, Slee AM and Kerr JS: An objective procedure for ischemic area evaluation of the stroke intraluminal thread model in the mouse and rat. J Neurosci Methods. 113:51–58. 2002.PubMed/NCBI View Article : Google Scholar
33	Ashwal S, Tone B, Tian HR, Cole DJ and Pearce WJ: Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke. 29:1037–1047. 1998.PubMed/NCBI View Article : Google Scholar
34	Zwerus R and Absalom A: Update on anesthetic neuroprotection. Curr Opin Anaesthesiol. 28:424–430. 2015.PubMed/NCBI View Article : Google Scholar
35	Thomazeau J, Rouquette A, Martinez V, Rabuel C, Prince N, Laplanche JL, Nizard R, Bergmann JF, Perrot S and Lloret-Linares C: Acute pain factors predictive of post-operative pain and opioid requirement in multimodal analgesia following knee replacement. Eur J Pain. 20:822–832. 2016.PubMed/NCBI View Article : Google Scholar
36	Murry CE, Richard VJ, Reimer KA and Jennings RB: Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res. 66:913–931. 1990.PubMed/NCBI View Article : Google Scholar
37	Schultz JE, Rose E, Yao Z and Gross GJ: Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol. 268:H2157–H2161. 1995.PubMed/NCBI View Article : Google Scholar
38	Gao CJ, Niu L, Ren PC, Wang W, Zhu C, Li YQ, Chai W and Sun XD: Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system. Neuroscience. 202:352–362. 2012.PubMed/NCBI View Article : Google Scholar
39	Zhao P, Huang Y and Zuo Z: Opioid preconditioning induces opioid receptor-dependent delayed neuroprotection against ischemia in rats. J Neuropathol Exp Neurol. 65:945–952. 2006.PubMed/NCBI View Article : Google Scholar
40	Liu Y, Li J, Yang J, Ji F, Bu X, Zhang N and Zhang B: Inhibition of PKCgamma membrane translocation mediated morphine preconditioning-induced neuroprotection against oxygen-glucose deprivation in the hippocampus slices of mice. Neurosci Lett. 444:87–91. 2008.PubMed/NCBI View Article : Google Scholar
41	Arabian M, Aboutaleb N, Soleimani M, Mehrjerdi FZ, Ajami M and Pazoki-Toroudi H: Role of morphine preconditioning and nitric oxide following brain ischemia reperfusion injury in mice. Iran J Basic Med Sci. 18:14–21. 2015.PubMed/NCBI
42	Peart JN and Gross GJ: Cardioprotective effects of acute and chronic opioid treatment are mediated via different signaling pathways. Am J Physiol Heart Circ Physiol. 291:H1746–H1753. 2006.PubMed/NCBI View Article : Google Scholar
43	Zhang N, Zhu H, Han S, Sui L and Li J: cPKCγ alleviates ischemic injury through modulating synapsin Ia/b phosphorylation in neurons of mice. Brain Res Bull. 142:156–162. 2018.PubMed/NCBI View Article : Google Scholar
44	Faubel S and Edelstein CL: Caspases as drug targets in ischemic organ injury. Curr Drug Targets Immune Endocr Metabol Disord. 5:269–287. 2005.PubMed/NCBI View Article : Google Scholar
45	Eftekhar-Vaghefi S, Esmaeili-Mahani S, Elyasi L and Abbasnejad M: Involvement of Mu opioid receptor signaling in the protective effect of opioid against 6-hydroxydopamine-induced SH-SY5Y human neuroblastoma cells apoptosis. Basic Clin Neurosci. 6:171–178. 2015.PubMed/NCBI
46	Arabian M, Aboutaleb N, Soleimani M, Ajami M, Habibey R, Rezaei Y and Pazoki-Toroudi H: Preconditioning with morphine protects hippocampal CA1 neurons from ischemia-reperfusion injury via activation of the mTOR pathway. Can J Physiol Pharmacol. 96:80–87. 2018.PubMed/NCBI View Article : Google Scholar
47	Lu S, Liao L, Zhang B, Yan W, Chen L, Yan H, Guo L, Lu S, Xiong K and Yan J: Antioxidant cascades confer neuroprotection in ethanol, morphine, and methamphetamine preconditioning. Neurochem Int. 131(104540)2019.PubMed/NCBI View Article : Google Scholar