Esketamine Provides Neuroprotection After Intracerebral Hemorrhage in Mice Via the NTF3/PI3K/AKT Pathway

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2024 Dec 18

PMID 39690816

Authors

Xiaoyu Niu

Yuanyuan Zheng

Wang Wang

Liwei Zhang

Shaoshuai Wang

Xihua Lu

Junyang Wang

Gaiqing Yang

Ting Zhao

Qiang Li

Nan Li

Junmin Wang

Jian Wang

Changsheng Li

Affiliations

Soon will be listed here.

Abstract

Background: Esketamine (ESK), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, modulates neurotransmitter signaling in the central nervous system. However, the specific mechanisms and therapeutic potential of ESK for intracerebral hemorrhage (ICH) remain unclear. This study aimed to investigate whether ESK promotes nerve repair and improves neurological outcomes in an experimental model of ICH.

Methods: ICH was induced in mice via collagenase injection into the striatum. Body weight, neurological impairment, and behavioral changes were assessed. ESK administration significantly improved several indicators of ICH. Comprehensive RNA transcriptome sequencing and network pharmacology analyses identified neurotrophin-3 (NTF3) and the PI3K/AKT signaling pathway as targets for ESK treatment. Western blotting and immunofluorescence detected the protein expression levels and cellular localization of NTF3.

Results: After 28 days of adeno-associated virus infection in the mouse striatum, ESK treatment significantly enhanced neuroprotection, indicating the crucial role of NTF3 in ESK-mediated neuroprotection in ICH mice. Inhibition of the PI3K/AKT pathway using the PI3K-specific inhibitor LY294002 significantly attenuated the therapeutic effects of ESK, suggesting that this pathway is involved in ESK-mediated neurorepair in ICH mice.

Conclusions: ESK treatment significantly improved functional outcomes and demonstrated neuroprotective effects in animal models of ICH. NTF3/PI3K/AKT pathway activation by ESK indicates its therapeutic potential in the treatment of ICH.

References

Chao M, Rajagopal R, Lee F . Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006; 110(2):167-73. DOI: 10.1042/CS20050163. View

Havlik J, Murphy M, Gong N, Tang D, Krystal J . Characteristics of Esketamine Prescribers Among Medicare Beneficiaries in the United States, 2019-2020. JAMA Netw Open. 2023; 6(4):e2311250. PMC: 10140803. DOI: 10.1001/jamanetworkopen.2023.11250. View

Jia P, He J, Li Z, Wang J, Jia L, Hao R . Profiling of Blood-Brain Barrier Disruption in Mouse Intracerebral Hemorrhage Models: Collagenase Injection vs. Autologous Arterial Whole Blood Infusion. Front Cell Neurosci. 2021; 15:699736. PMC: 8427528. DOI: 10.3389/fncel.2021.699736. View

Zhang Z, Li Y, Shi J, Zhu L, Dai Y, Fu P . Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage. Aging Dis. 2023; 14(3):966-991. PMC: 10187706. DOI: 10.14336/AD.2022.1102. View

Jia P, Wang J, Ren X, He J, Wang S, Xing Y . An enriched environment improves long-term functional outcomes in mice after intracerebral hemorrhage by mechanisms that involve the Nrf2/BDNF/glutaminase pathway. J Cereb Blood Flow Metab. 2023; 43(5):694-711. PMC: 10108193. DOI: 10.1177/0271678X221135419. View

Wang S, Ren X, Wang J, Peng Q, Niu X, Song C . Blocking autofluorescence in brain tissues affected by ischemic stroke, hemorrhagic stroke, or traumatic brain injury. Front Immunol. 2023; 14:1168292. PMC: 10258339. DOI: 10.3389/fimmu.2023.1168292. View

Li Q, Han X, Lan X, Gao Y, Wan J, Durham F . Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017; 2(7):e90777. PMC: 5374066. DOI: 10.1172/jci.insight.90777. View

Patapoutian A, Reichardt L . Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001; 11(3):272-80. DOI: 10.1016/s0959-4388(00)00208-7. View

Li F, Liu H, Zhang K, Xiao D, Wang C, Wang Y . Adipose-derived stromal cells improve functional recovery after spinal cord injury through TGF-β1/Smad3/PLOD2 pathway activation. Aging (Albany NY). 2021; 13(3):4370-4387. PMC: 7906172. DOI: 10.18632/aging.202399. View

10.

Maness L, Kastin A, Weber J, Banks W, Beckman B, Zadina J . The neurotrophins and their receptors: structure, function, and neuropathology. Neurosci Biobehav Rev. 1994; 18(1):143-59. DOI: 10.1016/0149-7634(94)90043-4. View

11.

Krafft P, Altay O, Rolland W, Duris K, Lekic T, Tang J . α7 nicotinic acetylcholine receptor agonism confers neuroprotection through GSK-3β inhibition in a mouse model of intracerebral hemorrhage. Stroke. 2011; 43(3):844-50. PMC: 3293395. DOI: 10.1161/STROKEAHA.111.639989. View

12.

Schatzberg A . Mechanisms of Action of Ketamine and Esketamine. Am J Psychiatry. 2021; 178(12):1130. DOI: 10.1176/appi.ajp.2021.21060653. View

13.

Reif A, Bitter I, Buyze J, Cebulla K, Frey R, Fu D . Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023; 389(14):1298-1309. DOI: 10.1056/NEJMoa2304145. View

14.

Gastaldon C, Raschi E, Kane J, Barbui C, Schoretsanitis G . Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2020; 90(1):41-48. DOI: 10.1159/000510703. View

15.

Adell A . Brain NMDA Receptors in Schizophrenia and Depression. Biomolecules. 2020; 10(6). PMC: 7355879. DOI: 10.3390/biom10060947. View

16.

Chen S, Peng J, Sherchan P, Ma Y, Xiang S, Yan F . TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice. J Neuroinflammation. 2020; 17(1):168. PMC: 7257134. DOI: 10.1186/s12974-020-01853-x. View

17.

Deng S, Jin P, Sherchan P, Liu S, Cui Y, Huang L . Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice. J Neuroinflammation. 2021; 18(1):62. PMC: 7923481. DOI: 10.1186/s12974-021-02112-3. View

18.

Hu D, Mo X, Luo J, Wang F, Huang C, Xie H . 17-DMAG ameliorates neuroinflammation and BBB disruption via SOX5 mediated PI3K/Akt pathway after intracerebral hemorrhage in rats. Int Immunopharmacol. 2023; 123:110698. DOI: 10.1016/j.intimp.2023.110698. View

19.

Su M, Zhu Y, Liu S, Song L, Qu J, Zhang Y . Median effective dose (ED) of esketamine combined with propofol for children to inhibit response of gastroscope insertion. BMC Anesthesiol. 2023; 23(1):240. PMC: 10354894. DOI: 10.1186/s12871-023-02204-y. View

20.

Bahji A, Vazquez G, Zarate Jr C . Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J Affect Disord. 2020; 278:542-555. PMC: 7704936. DOI: 10.1016/j.jad.2020.09.071. View