Pctx1 venom in the treatment of vasospasm due to experimental subarachnoidal hemorrhage

Year 2023, , 1230 - 1236, 29.10.2023

Mehmet Yigit Akgün , Mehmet Hüseyin Akgül

https://doi.org/10.32322/jhsm.1345021

Abstract

Aims: We aimed to investigate the role of neuron damage in experimental animals following vasospasm, by increasing perfusion of neuronal tissue through vasodilation using the venom of PcTx1, and to determine its effectiveness in reducing neuron damage after vasospasm.
Methods: Thirty adult male Wistar albino rats weighing between 300 and 400 grams were used and divided into three groups: the Sham group (Group 1, n=10), to which no application was made; the SAH (control) group (Group 2, n=10), in which a double SAH model was created and 1 cc of saline was administered intraperitoneally; and the SAH+PcTx1 group (Group 3, n=10), in which a double SAH model was created and 1 cc/kg of PcTx1 venom was administered intraperitoneally daily. Basilar artery diameter and immunochemical measurements were performed histopathologically, and neurohistopathological findings were scored semiquantitatively in terms of vascular changes, neuron degeneration, gliosis, and bleeding criteria using a scale of 0 (none), 1 (mild), 2 (moderate), or 3 (severe). eNOS immunopositivity was also evaluated. The detection of apoptosis in the brain was performed by evaluating the effector enzyme caspase-3 immunoreactivity of the exogenous apoptosis pathway.
Results: The most severe vascular spasm and degeneration-necrosis of brain tissue gray matter neurons were seen in Group 2, whereas the vascular narrowing was less severe in Group 3. Brain parenchyma and neuron and neuroglial reactions were milder in Group 3. eNOS expression was detected at a higher level in Group 1, Group 2, and Group 3, respectively. For apoptosis and caspase-3 immunoreactivity of the exogenous apoptosis pathway, no immunopositive reactions were observed in Group 1.
Conclusion: For the occurrence and formation mechanisms of vasospasm after subarachnoid hemorrhage, this pathological condition is thought to result from multifactorial and various biochemical reactions. In our study, it was found that psalmotoxin effectively prevented vasospasm and significantly reduced tissue damage after vasospasm.

Keywords

Experimental Subarachnoidal Hemorhage, Psalmotoxin, Venom, Vasospasm.

References

• Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke. 1998;29(1):251-256.
• Chalouhi N, Hoh BL, Hasan D. Review of cerebral aneurysm formation, growth, and rupture. Stroke. 2013;44(12):3613-3622.
• Etminan N, Rinkel GJ. Unruptured intracranial aneurysms: development, rupture and preventive management. Nat Rev Neurol. 2016;12(12):699-713.
• de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer TA, Abrahamson S, Macdonald RL. The critical care management of poor-grade subarachnoid haemorrhage. Crit Care. 2016;20:21.
• Mayberg MR, Batjer HH, Dacey R, et al. Guidelines for the management to aneurysmal subarachnoid hemorrhage. Stroke. 1994;25:2315-2328.
• Mocco J, Zacharia BE, Komotar RJ, Connolly ES Jr. A review of current and future medical therapies for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurosurg Focus. 2006;21(3):E9.
• Ingall T, Asplund K, Mahonen M, Bonita R. A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke. 2000;31:1054-1061.
• Behrouz R, Birnbaum LA, Jones PM, Topel CH, Misra V, Rabinstein AA. Focal neurological deficit at onset of aneurysmal subarachnoid hemorrhage: frequency and causes. J Stroke Cerebrovasc Dis. 2016; 25(11):2644-2647.
• Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke. 1994;25:1342-1347.
• Salary M, Quigley MR, Wilberger JE Jr. Relation among aneurysm size, amount of subarachnoid blood, and clinical outcome. J Neurosurg. 2007;107(1):13-7.
• Isaev NK, Stelmashook EV, Plotnikov EY, Khryapenkova TG, Lozier ER, Doludin YV. Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia. Biochem (Mosc). 2008;73(11):1171-1175.
• Xiong ZG, Chu XP, Simon RP. Acid sensing ion channelsdnovel therapeutic targets for ischemic brain injury. Front Biosci. 2007;12:1376-1386.
• Allen NJ, Attwell D. Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J Physiol. 2002;543(2):521-529.
• Krishtal O. The ASICs. signaling molecules? modulators? Trends Neurosci. 2003;26(9):477-83.
• Grunder S, Chen X. Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int J Physiol Pathophysiol Pharmacol. 2010;2(2):73-94.
• Papalampropoulou-Tsiridou M, Labrecque S, Godin AG, De Koninck Y, Wang F. Differential expression of acid – sensing ion channels in mouse primary afferents in native and injured conditions. Front Cell Neurosci. 2020;14:103.
• Wemmie JA, Price MP, Welsh MJ. Acid-sensing ion channels:advances, questions and therapeutic opportunities. Trends Neurosci. 2006;29(10):578-586.
• Escoubas P, De Weille JR, Lecoq A, et al. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem. 2000;275(33):25116-25121.
• Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL. Neuroprotection in ischemia:blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118(6):687-698.
• Pignataro G, Simon RP, Xiong Z. Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischemia. Brain. 2007;130(Pt 1):151-158.
• Li M, Inoue K, Branigan D, et al. Acid sensing ion channels in acidosis-induced injury of human brain neurons. J Cereb Blood Flow Metab. 2010;30(6):1247-1260.
• Origitano TC, Wascher TM, Reichman OH, Anderson DE. Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution ("triple-H" therapy) after subarachnoid hemorrhage. Neurosurgery. 1990;27(5):729-739.
• Wemmie JA, Taugher RJ, Kreple CJ. Acid-sensing ion channels in pain and disease. Nat Rev Neurosci. 2013;14(7):461-471
• Annunziato, Lucio. Sodium Calcium Exchange:A Growing Spectrum of Pathophysiological Implications:Proceedings of the 6th International Conference on Sodium Calcium Exchange. New York: Springer, 2013. Print.
• Muñoz-Guillén NM, León-López R, Túnez-Fiñana I, Cano-Sánchez A. From vasospasm to early brain injury:new frontiers in subarachnoid haemorrhage research. Neurologia. 2013;28(5):309-316.
• Kakumanu R, Hodgson WC, Ravi R, et al. Vampire venom: vasodilatory mechanisms of vampire bat (desmodus rotundus) blood feeding. Toxins (Basel). 2019;11(1):26.
• de Jesus-López E, Cuéllar-Balleza L, Díaz-Peña LF, Luna-Vázquez FJ, Ibarra-Alvarado C, García-Arredondo JA. Vasodilator activity of Poecilotheria ornata venom involves activation of the NO/cGMP pathway and inhibition of calcium influx to vascular smooth muscle cells. Toxicon X. 2023;19:100159.
• Konar SK, Ramesh S, Christopher R, et al. The correlation of endothelial nitric oxide synthase (eNOS) polymorphism and other risk factors with aneurysmal subarachnoid hemorrhage: a case-control study. Neurol India. 2019;67(4):1006-1012.
• Faraci FM, Taugher RJ, Lynch C, Fan R, Gupta S, Wemmie JA. Acid-sensing ion channels: novel mediators of cerebral vascular responses. Circ Res. 2019;125(10):907-920.
• Koehn LM, Noor NM, Dong Q, et al. Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury. F1000Res. 2016;5:1822.
• Wang J, Wang JF, Hu XM. Caspase-3 in serum predicts outcome after aneurysmal subarachnoid hemorrhage. Clin Chim Acta. 2016;460:196-202.
• Garcia SM, Naik JS, Resta TC, Jernigan NL. Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation. J Gen Physiol. 2023;155(2):e202213173.