Potential effect of physical exercise on the downregulation of BDNF mRNA expression in rat hippocampus following intracerebral hemorrhage.

OBJECTIVES: Physical exercise is known to induce expression of the neuroprotective brain derived neurotrophic factor (BDNF) in the hippocampus. This study examined the effects of physical exercise on hippocampal BDNF expression and the potential benefits for preventing remote secondary hippocampal damage and neurological impairment following intracerebral hemorrhage (ICH). MATERIALS AND METHODS: Wistar rats were randomly assigned to sham-operated, ICH, and ICH followed by exercise (ICH/Ex) groups. The two ICH groups were injected with type IV collagenase into the left basal ganglia, while sham animals were injected with equal-volume saline. The ICH/Ex group rats ran on a treadmill at 11 m/min for 30 min/day from day 3 to 16 post-ICH. All animals were examined for neurological function on day 2 pretreatment and from day 3 to 15 posttreatment, for spontaneous motor activity in the open field on day 15, and for cognitive ability using the object location test on day 16. Animals were then euthanized and bilateral hippocampi collected for gene expression analyses. RESULTS: Experimental ICH induced neurological deficits that were not reversed by exercise. In contrast, ICH did not alter spontaneous activity or object location ability. Expression of BDNF mRNA of the ICH group was significantly downregulated in the ipsilateral hippocampus compared to the SHAM group, but this downregulation was not shown in the ICH/Ex group. The ICH/Ex group showed the downregulation of caspase-3 mRNA expression in the contralateral hippocampus compared to the SHAM group, while neither ICH nor exercise influenced toll-like receptor 4 mRNA expression. CONCLUSIONS: ICH induced the secondary BDNF downregulation in the hippocampus remote from the lesion, whereas physical exercise might partially mitigate the downregulation.

Epigenetic modification of histone acetylation in the sensorimotor cortex after intracerebral hemorrhage.

Epigenetic regulation is involved in post-stroke neuroplasticity. We investigated the effects of intracerebral hemorrhage (ICH) on histone acetylation and gene expression related to neuronal plasticity in the bilateral sensorimotor cortices, which may affect post-stroke sensorimotor function. Wistar rats were randomly divided into the SHAM and ICH groups. We performed ICH surgery stereotaxically based on the microinjection of a collagenase solution in the ICH group. Foot fault and cylinder tests were performed to evaluate motor functions at 4-time points, including pre-ICH surgery. The amount of acetyl histones and the mRNA expression of neurotrophic factors crucial to neuroplasticity in the bilateral sensorimotor cortices were analyzed approximately 2 weeks after ICH surgery. Sensorimotor functions of the ICH group were inferior to those of the SHAM group during 2 weeks post-ICH. ICH increased the acetylation of histone H3 and H4 over the sham level in the ipsilateral and contralateral cortices. ICH increased the mRNA expression of IGF-1, but decreased the expression of BDNF compared with the sham level in the ipsilateral cortex. The present study suggests that histone acetylation levels are enhanced in bilateral sensorimotor cortices after ICH, presenting an altered epigenetic platform for gene expressions related to neuronal plasticity.

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

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.