Combined treatment with exercise and α5GABAAR inhibitor promotes motor function recovery after intracerebral hemorrhage.

Takahiro Inoue, Yasuyuki Takamatsu, Taichi Nishio, Kiho Soma, Misato Okamura, Harukazu Tohyama, Hiroshi Maejima

Neuroscience letters 2022 Jan 01

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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 (α5GABAAR) 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 α5GABAAR, 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 α5GABAAR 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. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Takahiro Inoue, Yasuyuki Takamatsu, Taichi Nishio, Kiho Soma, Misato Okamura, Harukazu Tohyama, Hiroshi Maejima. Combined treatment with exercise and α5GABAAR inhibitor promotes motor function recovery after intracerebral hemorrhage. Neuroscience letters. 2022 Jan 01;766:136344