Combined treatment with exercise and α5GABAAR inhibitor promotes motor function recovery after intracerebral hemorrhage. (1st January 2022)

• Record Type: Journal Article
• Authors: Inoue, Takahiro; Takamatsu, Yasuyuki; Nishio, Taichi; Soma, Kiho; Okamura, Misato; Tohyama, Harukazu; Maejima, Hiroshi
• Is Part Of: Neuroscience letters. Volume 766(2022)
• Publication Date: 2022-01-01
• Subjects: Exercise -- GABA -- Spinal cord -- Sprouting -- Stroke -- Synaptic plasticity; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2021.136344
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Combined treatment consisted of treadmill exercise and α5GABAA R inhibitor. Combined treatment effectively promoted motor function recovery after ICH. α5GABAA R inhibitor enhanced BDNF expression in the CNS. Combined treatment altered the neuroplastic marker expressions in the spinal cord. Abstract: The present study aimed to examine the synergistic effects of exercise and pharmacological inhibition of the α5 subunit-containing gamma-aminobutyric acid (GABA)A receptors (α5GABAA R) on motor function recovery after intracerebral hemorrhage (ICH). Wistar rats were divided into five groups ( n = 8 per group): SHAM, ICH, ICH + exercise (ICH + EX), ICH + L-655, 708 (ICH + L6), and ICH + L-655, 708 and exercise (ICH + L6EX) groups. ICH was induced by microinjection of a collagenase solution. The ICH + EX and ICH + L6EX groups exercised on a treadmill (12 m/min for 30 min/day). L-655, 708 (0.5 mg/kg), a negative allosteric modulator of α5GABAA R, was administered intraperitoneally to the ICH + L6 and ICH + L6EX groups. Each intervention was initiated 1 week after the ICH surgery and was performed for 3 weeks, followed by tissue collection, including the motor cortex and spinal cord. At 4 weeks after ICH, significant motor recovery was found in the ICH + L6EX group compared to the ICH group. L-655, 708 administration increased brain-derived neurotrophic factor (BDNF) expression in the cortex. Regarding neuroplastic changes in the spinal cord, rats in the ICH + L6EX group showed a significant increase in several neuroplastic markers: 1) BDNF, 2) growth-associated protein 43 as an axonal sprouting marker, 3) synaptophysin as a synaptic marker, and 4) Nogo-A as an axonal growth inhibitor. This study is the first to demonstrate that combined treatment with exercise and α5GABAA R inhibitor effectively promoted motor function recovery after ICH. Regarding the underlying mechanism of post-ICH recovery with the combined treatment, the present study highlights the importance of both growth and inhibitory modification of axonal sprouting in the spinal cord.