GABA Receptor Antagonist Promotes Hippocampal Neurogenesis and Facilitates Cognitive Function Recovery Following Acute Cerebral Ischemia in Mice

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2021 Jan 8

PMID 33413637

Citations 7

Authors

Dan Song

Yaohua Chen

Cheng Chen

Lili Chen

Oumei Cheng

Affiliations

Soon will be listed here.

Abstract

Purpose And Background: Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABA receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABA receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI.

Methods: Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABA receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot.

Results: CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs.

Conclusion: Inhibition of GABA receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

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References

Cheng O, Ostrowski R, Liu W, Zhang J . Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-kappaB. Neuroscience. 2010; 166(4):1101-9. PMC: 2833222. DOI: 10.1016/j.neuroscience.2010.01.024. View

Chen L, Song D, Chen B, Yang X, Cheng O . Activation of liver X receptor promotes hippocampal neurogenesis and improves long-term cognitive function recovery in acute cerebral ischemia-reperfusion mice. J Neurochem. 2019; 154(2):205-217. DOI: 10.1111/jnc.14890. View

Gould E . How widespread is adult neurogenesis in mammals?. Nat Rev Neurosci. 2007; 8(6):481-8. DOI: 10.1038/nrn2147. View

Lanza M, Fassio A, Gemignani A, Bonanno G, Raiteri M . CGP 52432: a novel potent and selective GABAB autoreceptor antagonist in rat cerebral cortex. Eur J Pharmacol. 1993; 237(2-3):191-5. DOI: 10.1016/0014-2999(93)90268-m. View

Ming G, Song H . Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci. 2005; 28:223-50. DOI: 10.1146/annurev.neuro.28.051804.101459. View

Dillen Y, Kemps H, Gervois P, Wolfs E, Bronckaers A . Adult Neurogenesis in the Subventricular Zone and Its Regulation After Ischemic Stroke: Implications for Therapeutic Approaches. Transl Stroke Res. 2019; 11(1):60-79. DOI: 10.1007/s12975-019-00717-8. View

Alvarez-Buylla A, Lim D . For the long run: maintaining germinal niches in the adult brain. Neuron. 2004; 41(5):683-6. DOI: 10.1016/s0896-6273(04)00111-4. View

Mayor D, Tymianski M . Neurotransmitters in the mediation of cerebral ischemic injury. Neuropharmacology. 2017; 134(Pt B):178-188. DOI: 10.1016/j.neuropharm.2017.11.050. View

Song J, Zhong C, Bonaguidi M, Sun G, Hsu D, Gu Y . Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature. 2012; 489(7414):150-4. PMC: 3438284. DOI: 10.1038/nature11306. View

10.

Komitova M, Mattsson B, Johansson B, Eriksson P . Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke. 2005; 36(6):1278-82. DOI: 10.1161/01.STR.0000166197.94147.59. View

11.

Tian L, Nie H, Zhang Y, Chen Y, Peng Z, Cai M . Recombinant human thioredoxin-1 promotes neurogenesis and facilitates cognitive recovery following cerebral ischemia in mice. Neuropharmacology. 2013; 77:453-64. DOI: 10.1016/j.neuropharm.2013.10.027. View

12.

Chojnacki A, Weiss S . Production of neurons, astrocytes and oligodendrocytes from mammalian CNS stem cells. Nat Protoc. 2008; 3(6):935-40. DOI: 10.1038/nprot.2008.55. View

13.

Wu C, Zhan R, Qi S, Fujihara H, Taga K, Shimoji K . A forebrain ischemic preconditioning model established in C57Black/Crj6 mice. J Neurosci Methods. 2001; 107(1-2):101-6. DOI: 10.1016/s0165-0270(01)00356-9. View

14.

He W, Ying-Fu L, Wang H, Peng Y . Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model. Sci Rep. 2019; 9(1):2287. PMC: 6381084. DOI: 10.1038/s41598-019-38750-0. View

15.

Jiao J, Chen D . Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals. Stem Cells. 2008; 26(5):1221-30. PMC: 2683670. DOI: 10.1634/stemcells.2007-0513. View

16.

Wang Y, Dzyubenko E, Sanchez-Mendoza E, Sardari M, de Carvalho T, Doeppner T . Postacute Delivery of GABA α5 Antagonist Promotes Postischemic Neurological Recovery and Peri-infarct Brain Remodeling. Stroke. 2018; 49(10):2495-2503. PMC: 6159671. DOI: 10.1161/STROKEAHA.118.021378. View

17.

Zhu X, Hu H, Li Z, Lin R, Mao J, Chen L . Gua Lou Gui Zhi decoction attenuates post‑stroke spasticity via the modulation of GABAB receptors. Mol Med Rep. 2015; 12(4):5957-62. DOI: 10.3892/mmr.2015.4207. View

18.

Zhang H, Yuan L, Zhao R, Tong L, Ma R, Dong H . Isoflurane preconditioning induces neuroprotection by attenuating ubiquitin-conjugated protein aggregation in a mouse model of transient global cerebral ischemia. Anesth Analg. 2010; 111(2):506-14. DOI: 10.1213/ANE.0b013e3181e45519. View

19.

Liu J, Solway K, Messing R, Sharp F . Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci. 1998; 18(19):7768-78. PMC: 6793017. View

20.

Reynolds B, Tetzlaff W, Weiss S . A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci. 1992; 12(11):4565-74. PMC: 6575989. View