α7 Nicotinic Acetylcholine Receptor Agonist Improved Brain Injury and Impaired Glucose Metabolism in a Rat Model of Ischemic Stroke

Overview

Journal Metab Brain Dis

Publisher Springer

Specialties Endocrinology
Neurology

Date 2023 Jan 20

PMID 36662413

Authors

Ya-Yu Wang

Shih-Yi Lin

Cheng-Yi Chang

Chih-Cheng Wu

Wen-Ying Chen

Wei-Chi Huang

Su-Lan Liao

Wen-Yi Wang

Chun-Jung Chen

Affiliations

Soon will be listed here.

Abstract

Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.

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References

Abbas M, Alzarea S, Papke R, Rahman S . The α7 nicotinic acetylcholine receptor positive allosteric modulator prevents lipopolysaccharide-induced allodynia, hyperalgesia and TNF-α in the hippocampus in mice. Pharmacol Rep. 2019; 71(6):1168-1176. PMC: 7745232. DOI: 10.1016/j.pharep.2019.07.001. View

Amin E, Rifaai R, Abdel-Latif R . Empagliflozin attenuates transient cerebral ischemia/reperfusion injury in hyperglycemic rats via repressing oxidative-inflammatory-apoptotic pathway. Fundam Clin Pharmacol. 2020; 34(5):548-558. DOI: 10.1111/fcp.12548. View

Axelrod C, Fealy C, Erickson M, Davuluri G, Fujioka H, Dantas W . Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans. Metabolism. 2021; 121:154803. PMC: 8277749. DOI: 10.1016/j.metabol.2021.154803. View

Ay I, Lu J, Ay H, Sorensen A . Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett. 2009; 459(3):147-51. DOI: 10.1016/j.neulet.2009.05.018. View

Barron S, Rogovski Z, Hemli J . Autonomic consequences of cerebral hemisphere infarction. Stroke. 1994; 25(1):113-6. DOI: 10.1161/01.str.25.1.113. View

Broocks G, Jafarov H, McDonough R, Austein F, Meyer L, Bechstein M . Relationship between the degree of recanalization and functional outcome in acute ischemic stroke is mediated by penumbra salvage volume. J Neurol. 2021; 268(6):2213-2222. PMC: 8179901. DOI: 10.1007/s00415-021-10410-2. View

Carandina A, Lazzeri G, Villa D, Di Fonzo A, Bonato S, Montano N . Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke. Int J Mol Sci. 2021; 22(5). PMC: 7956667. DOI: 10.3390/ijms22052357. View

Catania A, Lonati C, Sordi A, Gatti S . Detrimental consequences of brain injury on peripheral cells. Brain Behav Immun. 2009; 23(7):877-84. DOI: 10.1016/j.bbi.2009.04.006. View

Czura C, Tracey K . Autonomic neural regulation of immunity. J Intern Med. 2005; 257(2):156-66. DOI: 10.1111/j.1365-2796.2004.01442.x. View

10.

Dong L, Ma Y, Xu J, Guo Y, Yang L, Guo F . Effect of hyperglycemia on microglial polarization after cerebral ischemia-reperfusion injury in rats. Life Sci. 2021; 279:119660. DOI: 10.1016/j.lfs.2021.119660. View

11.

Franke M, Bieber M, Kraft P, Weber A, Stoll G, Schuhmann M . The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice. Brain Behav Immun. 2020; 92:223-233. DOI: 10.1016/j.bbi.2020.12.009. View

12.

Frankenberg N, Mason S, Wadley G, Murphy R . Skeletal muscle cell-specific differences in type 2 diabetes. Cell Mol Life Sci. 2022; 79(5):256. PMC: 9035013. DOI: 10.1007/s00018-022-04265-7. View

13.

Gergalova G, Lykhmus O, Kalashnyk O, Koval L, Chernyshov V, Kryukova E . Mitochondria express α7 nicotinic acetylcholine receptors to regulate Ca2+ accumulation and cytochrome c release: study on isolated mitochondria. PLoS One. 2012; 7(2):e31361. PMC: 3281078. DOI: 10.1371/journal.pone.0031361. View

14.

Han Z, Li L, Wang L, Degos V, Maze M, Su H . Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress, and brain injury in mice with ischemic stroke and bone fracture. J Neurochem. 2014; 131(4):498-508. PMC: 4221541. DOI: 10.1111/jnc.12817. View

15.

Han Z, Shen F, He Y, Degos V, Camus M, Maze M . Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress. PLoS One. 2014; 9(8):e105711. PMC: 4144901. DOI: 10.1371/journal.pone.0105711. View

16.

Hua S, Ek C, Mallard C, Johansson M . Perinatal hypoxia-ischemia reduces α 7 nicotinic receptor expression and selective α 7 nicotinic receptor stimulation suppresses inflammation and promotes microglial Mox phenotype. Biomed Res Int. 2014; 2014:718769. PMC: 3976804. DOI: 10.1155/2014/718769. View

17.

Isayama K, Pitts L, Nishimura M . Evaluation of 2,3,5-triphenyltetrazolium chloride staining to delineate rat brain infarcts. Stroke. 1991; 22(11):1394-8. DOI: 10.1161/01.str.22.11.1394. View

18.

Jheng H, Tsai P, Guo S, Kuo L, Chang C, Su I . Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol. 2011; 32(2):309-19. PMC: 3255771. DOI: 10.1128/MCB.05603-11. View

19.

Jiang Y, Li L, Liu B, Zhang Y, Chen Q, Li C . Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat. PLoS One. 2014; 9(7):e102342. PMC: 4103831. DOI: 10.1371/journal.pone.0102342. View

20.

Kashiwagi S, Khan M, Yasuhara S, Goto T, Kem W, Tompkins R . Prevention of Burn-Induced Inflammatory Responses and Muscle Wasting by GTS-21, a Specific Agonist for α7 Nicotinic Acetylcholine Receptors. Shock. 2016; 47(1):61-69. PMC: 5167674. DOI: 10.1097/SHK.0000000000000729. View