Abstract
Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.
Similar content being viewed by others
Data Availability
The datasets generated and/or analyzed during the current study are available in the manuscript.
References
Novak CM, Ozen M, Burd I (2018) Perinatal brain injury: mechanisms, prevention, and outcomes. Clin Perinatol 45(2):357–375. https://doi.org/10.1016/j.clp.2018.01.015
Sanchez-Illana A, Pineiro-Ramos JD, Kuligowski J (2020) Small molecule biomarkers for neonatal hypoxic ischemic encephalopathy. Semin Fetal Neonatal Med 25(2):101084. https://doi.org/10.1016/j.siny.2020.101084
Kurinczuk JJ, White-Koning M, Badawi N (2010) Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 86(6):329–338. https://doi.org/10.1016/j.earlhumdev.2010.05.010
Lai MC, Yang SN (2011) Perinatal hypoxic-ischemic encephalopathy. J Biomed Biotechnol 2011:609813. https://doi.org/10.1155/2011/609813
Perlman M, Shah PS (2011) Hypoxic-ischemic encephalopathy: challenges in outcome and prediction. J Pediatr 158(2 Suppl):e51-54. https://doi.org/10.1016/j.jpeds.2010.11.014
Douglas-Escobar M, Weiss MD (2012) Biomarkers of brain injury in the premature infant. Front Neurol 3:185. https://doi.org/10.3389/fneur.2012.00185
Huang WQ, Zhang W, Liu WW (2020) Research progress in drug therapy for neonatal hypoxic ischemic encephalopathy. Med Recapotulate 26(22):4457–4461. https://doi.org/10.3969/j.issn.1006-2084.2020.22.017
Narayanamurthy R, Yang JJ, Yager JY, Unsworth LD (2021) Drug delivery platforms for neonatal brain injury. J Control Release 330:765–787. https://doi.org/10.1016/j.jconrel.2020.12.056
Zou R, Mu DZ (2016) prevention and treatment of energy failure in neonates with hypoxic-ischemic encephalopathy. Zhongguo Dang Dai Er Ke Za Zhi 18(9):915–920. https://doi.org/10.7499/j.issn.1008-8830.2016.09.024
Adstamongkonkul D, Hess DC (2017) Ischemic conditioning and neonatal hypoxic ischemic encephalopathy: a literature review. Cond Med 1(1):9–16
Bhalala US, Koehler RC, Kannan S (2014) Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front Pediatr 2:144. https://doi.org/10.3389/fped.2014.00144
Douglas-Escobar M, Weiss MD (2015) Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr 169(4):397–403. https://doi.org/10.1001/jamapediatrics.2014.3269
Zhu JC, Peng ZH, Teng XF et al (2016) Efficacy of het0016 for improving delayed mild hypothermia-induced protection of rat neurons subjected to oxygen-glucose deprivation and restoration in vitro. Chin J Anesthesiol 36(4):484–487. https://doi.org/10.3760/cma.j.issn.0254-1416.2016.04.027
Zhu JC, Bai WY, Yang YC et al (2016) Effect of het0016 combined with mild hypothermia on expression of m-calpain protein in cerebral neurons of neonatal piglets with hypoxic-ischemic encephalopathy. Chin J Anesthesiol 36:505–507. https://doi.org/10.3760/cma.j.issn.0254-1416.2016.04.033
Perrin BJ, Huttenlocher A (2002) Calpain. Int J Biochem Cell Biol 34(7):722–725. https://doi.org/10.1016/s1357-2725(02)00009-2
Khan H, Garg N, Singh TG, Kaur A, Thapa K (2022) Calpain inhibitors as potential therapeutic modulators in neurodegenerative diseases. Neurochem Res 47(5):1125–1149. https://doi.org/10.1007/s11064-021-03521-9
Wu HY, Lynch DR (2006) Calpain and synaptic function. Mol Neurobiol 33(3):215–236. https://doi.org/10.1385/MN:33:3:215
Baudry M, Bi X (2016) Calpain-1 and calpain-2: the yin and yang of synaptic plasticity and neurodegeneration. Trends Neurosci 39(4):235–245. https://doi.org/10.1016/j.tins.2016.01.007
Shinkai-Ouchi F, Shindo M, Doi N, Hata S, Ono Y (2020) Calpain-2 participates in the process of calpain-1 inactivation. Biosci Rep 40(11):BSR20200552. https://doi.org/10.1042/BSR20200552
Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83(3):731–801. https://doi.org/10.1152/physrev.00029.2002
Dokus LE, Yousef M, Banoczi Z (2020) Modulators of calpain activity: inhibitors and activators as potential drugs. Expert Opin Drug Discov 15(4):471–486. https://doi.org/10.1080/17460441.2020.1722638
Salazar IL, Caldeira MV, Curcio M, Duarte CB (2016) The role of proteases in hippocampal synaptic plasticity: putting together small pieces of a complex puzzle. Neurochem Res 41(1–2):156–182. https://doi.org/10.1007/s11064-015-1752-5
Sorimachi H, Mamitsuka H, Ono Y (2012) Understanding the substrate specificity of conventional calpains. Biol Chem 393(9):853–871. https://doi.org/10.1515/hsz-2012-0143
Zatz M, Starling A (2005) Calpains and disease. N Engl J Med 352(23):2413–2423. https://doi.org/10.1056/NEJMra043361
Kuang CS, Xu H, Huang Z et al (2015) The protective effect of calpain inhibitor against focal cerebral ischemia-reperfusion injury in rats. Med Innov China 12(28):15–18. https://doi.org/10.3969/j.issn.1674-4985.2015.28.005
Li H, Zhang N, Sun G, Ding S (2013) Inhibition of the group I mGluRs reduces acute brain damage and improves long-term histological outcomes after photothrombosis-induced ischaemia. ASN Neuro 5(3):195–207. https://doi.org/10.1042/AN20130002
Zheng B, Wu X, Yang L (2011) Dynamic changes of calpain1 and calpain2 after traumatic brain injury in rats. China Med Univ 26(1):13–15
Cao X, Zhang Y, Zou L, Xiao H, Chu Y, Chu X (2010) Persistent oxygen-glucose deprivation induces astrocytic death through two different pathways and calpain-mediated proteolysis of cytoskeletal proteins during astrocytic oncosis. Neurosci Lett 479(2):118–122. https://doi.org/10.1016/j.neulet.2010.05.040
Brodhun M, Fritz H, Walter B, Antonow-Schlorke I, Reinhart K, Zwiener U, Bauer R, Patt S (2001) Immunomorphological sequelae of severe brain injury induced by fluid-percussion in juvenile pigs–effects of mild hypothermia. Acta Neuropathol 101(5):424–434. https://doi.org/10.1007/s004010000290
Sandsmark DK, Bashir A, Wellington CL, Diaz-Arrastia R (2019) Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron 103(3):367–379. https://doi.org/10.1016/j.neuron.2019.06.002
Gamdzyk M, Doycheva DM, Araujo C, Ocak U, Luo Y, Tang J, Zhang JH (2020) cGAS/STING pathway activation contributes to delayed neurodegeneration in neonatal hypoxia-ischemia rat model: possible involvement of LINE-1. Mol Neurobiol 57(6):2600–2619. https://doi.org/10.1007/s12035-020-01904-7
Hausburg MA, Banton KL, Roman PE, Salgado F, Baek P, Waxman MJ, Tanner A 2nd, Yoder J et al (2020) Effects of propofol on ischemia-reperfusion and traumatic brain injury. J Crit Care 56:281–287. https://doi.org/10.1016/j.jcrc.2019.12.021
Shi H, Yu Y, Liu X, Yu Y, Li M, Wang Y, Zou Y, Chen R (2022) Inhibition of calpain reduces cell apoptosis by suppressing mitochondrial fission in acute viral myocarditis. Cell Biol Toxicol 38(3):487–504. https://doi.org/10.1007/s10565-021-09634-9
Raynaud F, Marcilhac A (2006) Implication of calpain in neuronal apoptosis. A possible regulation of Alzheimer’s disease. FEBS J 273(15):3437–3443. https://doi.org/10.1111/j.1742-4658.2006.05352.x
Kambe A, Yokota M, Saido TC, Satokata I, Fujikawa H, Tabuchi S, Kamitani H, Watanabe T (2005) Spatial resolution of calpain-catalyzed proteolysis in focal cerebral ischemia. Brain Res 1040(1–2):36–43. https://doi.org/10.1016/j.brainres.2005.01.080
Rami A, Agarwal R, Botez G, Winckler J (2000) mu-Calpain activation, DNA fragmentation, and synergistic effects of caspase and calpain inhibitors in protecting hippocampal neurons from ischemic damage. Brain Res 866(1–2):299–312. https://doi.org/10.1016/s0006-8993(00)02301-5
Zhang C, Siman R, Xu YA, Mills AM, Frederick JR, Neumar RW (2002) Comparison of calpain and caspase activities in the adult rat brain after transient forebrain ischemia. Neurobiol Dis 10(3):289–205. https://doi.org/10.1006/nbdi.2002.0526
Blomgren K, McRae A, Elmered A, Bona E, Kawashima S, Saido TC, Ono T, Hagberg H (1997) The calpain proteolytic system in neonatal hypoxic-ischemia. Ann N Y Acad Sci 825:104–119. https://doi.org/10.1111/j.1749-6632.1997.tb48420.x
Kawamura M, Nakajima W, Ishida A, Ohmura A, Miura S, Takada G (2005) Calpain inhibitor MDL 28170 protects hypoxic-ischemic brain injury in neonatal rats by inhibition of both apoptosis and necrosis. Brain Res 1037(1–2):59–69. https://doi.org/10.1016/j.brainres.2004.12.050
Mellgren RL (1997) Evidence for participation of a calpain-like cysteine protease in cell cycle progression through late G1 phase. Biochem Biophys Res Commun 236(3):555–558. https://doi.org/10.1006/bbrc.1997.7003
Jia SZ, Xu XW, Zhang ZH, Chen C, Chen Y-B, Huang S-L, Liu Q, Hoffmann P-R et al (2021) Selenoprotein K deficiency-induced apoptosis: a role for calpain and the ERS pathway. Redox Biol 47:102154. https://doi.org/10.1016/j.redox.2021.102154
Xie RJ, Hu XX, Zheng L, Cai S, Chen Y-S, Yang Y, Yang T, Han B et al (2020) Calpain-2 activity promotes aberrant endoplasmic reticulum stress-related apoptosis in hepatocytes. World J Gastroenterol 26(13):1450–1462. https://doi.org/10.3748/wjg.v26.i13.1450
Peintner L, Venkatraman A, Waeldin A, Hofherr A, Busch T, Voronov A, Viau A, Kuehn EW et al (2021) Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner. Autophagy 17(9):2384–2400. https://doi.org/10.1080/15548627.2020.1826716
Yamashima T, Tonchev AB, Tsukada T, Saido TC, Imajoh-Ohmi S, Momoi T, Kominami E (2003) Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates. Hippocampus 13(7):791–800. https://doi.org/10.1002/hipo.10127
Yamashima T (2004) Ca2+-dependent proteases in ischemic neuronal death: a conserved “calpain-cathepsin cascade” from nematodes to primates. Cell Calcium 36(3–4):285–293. https://doi.org/10.1016/j.ceca.2004.03.001
Yamashima T, Oikawa S (2009) The role of lysosomal rupture in neuronal death. Prog Neurobiol 89(4):343–358. https://doi.org/10.1016/j.pneurobio.2009.09.003
Hossain MI, Marcus JM, Lee JH, Garcia PL, Singh V, Shacka JJ, Zhang J, Gropen TI et al (2021) Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective. Autophagy 17(6):1330–1348. https://doi.org/10.1080/15548627.2020.1761219
Yamashima T (2016) Can “calpain-cathepsin hypothesis” explain Alzheimer neuronal death? Ageing Res Rev 32:169–179. https://doi.org/10.1016/j.arr.2016.05.008
Knopp RC, Jastaniah A, Dubrovskyi O, Gaisina I, Tai L, Thatcher GRJ (2021) Extending the calpain-cathepsin hypothesis to the neurovasculature: protection of brain endothelial cells and mice from neurotrauma. ACS Pharmacol Transl Sci 4(1):372–385. https://doi.org/10.1021/acsptsci.0c00217
Martinez-Alonso E, Guerra-Perez N, Escobar-Peso A, Peracho L, Vera-Lechuga R, Cruz-Culebras A, Masjuan J, Alcázar A (2022) Phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1147 is specific for eIF4G1 bound to eIF4E in delayed neuronal death after ischemia. Int J Mol Sci 23(3):1830. https://doi.org/10.3390/ijms23031830
White BC, Sullivan JM, DeGracia DJ, O’Neil BJ, Neumar RW, Grossman LI, Rafols JA, Krause GS (2000) Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 179(S 1-2):1–33. https://doi.org/10.1016/s0022-510x(00)00386-5
Westenbroek RE, Bausch SB, Lin RC, Franck JE, Noebels JL, Catterall WA (1998) Upregulation of L-type Ca2+ channels in reactive astrocytes after brain injury, hypomyelination, and ischemia. J Neurosci 18(7):2321–2334. https://doi.org/10.1523/JNEUROSCI.18-07-02321.1998
Bevers MB, Neumar RW (2008) Mechanistic role of calpains in postischemic neurodegeneration. J Cereb Blood Flow Metab 28(4):655–673. https://doi.org/10.1038/sj.jcbfm.9600595
Barnoy S, Zipser Y, Glaser T, Grimberg Y, Kosower NS (1999) Association of calpain (Ca(2+)-dependent thiol protease) with its endogenous inhibitor calpastatin in myoblasts. J Cell Biochem 74(4):522–531. https://doi.org/10.1002/(sici)1097-4644(19990915)74:4%3c522::aid-jcb2%3e3.3.co;2-9
Parr T, Sensky PL, Bardsley RG, Buttery PJ et al (2001) Calpastatin expression in porcine cardiac and skeletal muscle and partial gene structure. Arch Biochem Biophys 395(1):1–13. https://doi.org/10.1006/abbi.2001.2546
Parr T, Jewell KK, Sensky PL, Brameld JM, Brameld JM, Buttery PJ (2004) Expression of calpastatin isoforms in muscle and functionality of multiple calpastatin promoters. Arch Biochem Biophys 427(1):8–15. https://doi.org/10.1016/j.abb.2004.04.001
Wendt A, Thompson VF, Goll DE (2004) Interaction of calpastatin with calpain: a review. Biol Chem 385(6):465–472. https://doi.org/10.1515/BC.2004.054
Nian H, Ma B (2021) Calpain-calpastatin system and cancer progression. Biol Rev Camb Philos Soc 96(3):961–975. https://doi.org/10.1111/brv.12686
Yang J, Weimer RM, Kallop D, Olsen O, Wu Z, Renier N, Uryu K, Tessier-Lavigne M (2013) Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin. Neuron 80(5):1175–1189. https://doi.org/10.1016/j.neuron.2013.08.034
Kotova IM, Pestereva NS, Traktirov DS, Absalyamova MT, Karpenko MN (2023) Functions and distribution of calpain-calpastatin system components in brain during mammal ontogeny. Biochim Biophys Acta Gen Subj 1867 5:130345. https://doi.org/10.1016/j.bbagen.2023.130345
Ray SK, Banik NL (2003) Calpain and its involvement in the pathophysiology of CNS injuries and diseases: therapeutic potential of calpain inhibitors for prevention of neurodegeneration. Curr Drug Targets CNS Neurol Disord 2(3):173–189. https://doi.org/10.2174/1568007033482887
Blomgren K (1999) Calpastatin is upregulated and acts as a suicide substrate to calpains in neonatal rat hypoxia-ischemia. Ann N Y Acad Sci 890:270–271. https://doi.org/10.1111/j.1749-6632.1999.tb08002.x
Higuchi M, Tomioka M, Takano J, Shirotani K, Iwata N, Masumoto H, Maki M, Itohara S et al (2005) Distinct mechanistic roles of calpain and caspase activation in neurodegeneration as revealed in mice overexpressing their specific inhibitors. J Biol Chem 280(15):15229–15237. https://doi.org/10.1074/jbc.M500939200
Guo A, Hall D, Zhang C, Peng T, Miller JD, Kutschke W, Grueter CE, Johnson FL et al (2015) Molecular determinants of calpain-dependent cleavage of junctophilin-2 protein in cardiomyocytes. J Biol Chem 290(29):17946–17955. https://doi.org/10.1074/jbc.M115.652396
Al Z, Cohen CM (1993) Phorbol 12-myristate 13-acetate-stimulated phosphorylation of erythrocyte membrane skeletal proteins is blocked by calpain inhibitors: possible role of protein kinase M. Biochem J 296(Pt 3):675–683. https://doi.org/10.1042/bj2960675
Liu T, Schneider RA, Shah V, Huang Y, Likhotvorik RI, Keshvara L, Hoyt DG (2009) Protein never in mitosis gene A interacting-1 regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells. J Inflamm (Lond) 6:20. https://doi.org/10.1186/1476-9255-6-20
Cho S, Liu D, Fairman D, Jenkins Li P, McGonigle P, Wood A (2004) Spatiotemporal evidence of apoptosis-mediated ischemic injury in organotypic hippocampal slice cultures. Neurochem Int 45(1):117–127. https://doi.org/10.1016/j.neuint.2003.11.012
Alavez S, Moran J, Franco-Cea A, Ortega-Gómez A, Casaletti L, Cameron LC (2004) Myosin Va is proteolysed in rat cerebellar granule neurons after excitotoxic injury. Neurosci Lett 367(3):404–409. https://doi.org/10.1016/j.neulet.2004.06.043
Kupina NC, Nath R, Bernath EE, Inoue J, Mitsuyoshi A, Yuen PW, Wang KK, Hall ED (2001) The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury. J Neurotrauma 18(11):1229–1240. https://doi.org/10.1089/089771501317095269
Buki A, Farkas O, Doczi T, Povlishock JT (2003) Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury. J Neurotrauma 20(3):261–268. https://doi.org/10.1089/089771503321532842
Arataki S, Tomizawa K, Moriwaki A, Nishida K, Matsushita M, Ozaki T, Kunisada T, Yoshida A et al (2005) Calpain inhibitors prevent neuronal cell death and ameliorate motor disturbances after compression-induced spinal cord injury in rats. J Neurotrauma 22(3):398–406. https://doi.org/10.1089/neu.2005.22.398
Seki T, Wang MH, Miyata N, Laniado-Schwartzman M (2005) Cytochrome P450 4A isoform inhibitory profile of N-hydroxy-N’-(4-butyl-2-methylphenyl)-formamidine (HET0016), a selective inhibitor of 20-HETE synthesis. Biol Pharm Bull 28(9):1651–1654. https://doi.org/10.1248/bpb.28.1651
Shi YW, Wu X, Qu Y et al (2022) Het0016 alleviates brain injury by inhibiting excessive autophagy after traumatic brain injury. Journal of Air Force Medical University 43(4):415–418
Degterev A, Yuan J (2008) Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 9(5):378–390. https://doi.org/10.1038/nrm2393
Yang ZJ, Carter EL, Kibler KK, Kwansa H, Crafa DA, Martin LJ, Roman RJ, Harder DR et al (2012) Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor. J Neurochem 121(1):168–179. https://doi.org/10.1111/j.1471-4159.2012.07666.x
Zeng Z, Zhang Y, Jiang W, He L, Qu H (2020) Modulation of autophagy in traumatic brain injury. J Cell Physiol 235(3):1973–1985. https://doi.org/10.1002/jcp.29173
Poloyac SM, Zhang Y, Bies RR, Kochanek PM, Graham SH (2006) Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia. J Cereb Blood Flow Metab 26(12):1551–1561. https://doi.org/10.1038/sj.jcbfm.9600309
Zhao XC, An P, Wu XY (2014) Role of het0016 in mice with col1agenase-induced intracerebral hemorrhage. Prog Anat Sci 1:5
Shu S, Zhang Z, Spicer D, Kulikowicz E, Hu K, Babapoor-Farrokhran S, Kannan S, Koehler RC et al (2019) Administration of a 20-hydroxyeicosatetraenoic acid synthesis inhibitor improves outcome in a rat model of pediatric traumatic brain injury. Dev Neurosci 41(3–4):166–176. https://doi.org/10.1159/000500895
Gao H, Cao Y, Xia H, Zhu X, Jin Y (2020) CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROS-induced lipid peroxidation and inflammation. Int J Mol Med 45(4):1121–1129. https://doi.org/10.3892/ijmm.2020.4479
Han X, Zhao X, Lan X, Li Q, Gao Y, Liu X, Wan J, Yang Z et al (2019) 20-HETE synthesis inhibition promotes cerebral protection after intracerebral hemorrhage without inhibiting angiogenesis. J Cereb Blood Flow Metab 39(8):1531–1543. https://doi.org/10.1177/0271678X18762645
Yildiz EP, Ekici B, Tatli B (2017) Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment. Expert Rev Neurother 17(5):449–459. https://doi.org/10.1080/14737175.2017.1259567
O’Mara K, McPherson C (2021) Neuroprotective agents for neonates with hypoxic-ischemic encephalopathy. Neonatal Netw 40(6):406–413. https://doi.org/10.1891/11-T-755
Natarajan G, Pappas A, Shankaran S (2016) Outcomes in childhood following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). Semin Perinatol 40(8):549–555. https://doi.org/10.1053/j.semperi.2016.09.007
Donkor IO (2011) Calpain inhibitors: a survey of compounds reported in the patent and scientific literature. Expert Opin Ther Pat 21(5):601–636. https://doi.org/10.1517/13543776.2011.568480
Donkor IO (2020) An update on the therapeutic potential of calpain inhibitors: a patent review. Expert Opin Ther Pat 30(9):659–675. https://doi.org/10.1080/13543776.2020.1797678
Ji J, Su L, Liu Z (2016) Critical role of calpain in inflammation. Biomed Rep 5(6):647–652. https://doi.org/10.3892/br.2016.785
Kumar V, Ahmad A (2017) Targeting calpains: a novel immunomodulatory approach for microbial infections. Eur J Pharmacol 814:28–44. https://doi.org/10.1016/j.ejphar.2017.08.002
Gao A, Mcoy HM, Zaman V, Shields DC, Banik NL, Haque A (2022) Calpain activation and progression of inflammatory cycles in Parkinson’s disease. Front Biosci (Landmark edition) 27:20. https://doi.org/10.31083/j.fbl2701020
Author information
Authors and Affiliations
Contributions
Ruiyang Zhao designed the study and drafted the manuscript. Xiufei Teng and Yanchao Yang collated the data, carried out data analyses, and produced the initial draft of the manuscript. All authors have read and approved the final submitted manuscript.
Corresponding author
Ethics declarations
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Research Involving Human Participants and/or Animals
Not applicable.
Informed Consent
Not applicable.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhao, R., Teng, X. & Yang, Y. Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy. Mol Neurobiol 61, 533–540 (2024). https://doi.org/10.1007/s12035-023-03594-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-023-03594-3