In vivo bioluminescence imaging revealed the change of the time window of BDNF expression in the brain elicited by a single bout of exercise following repeated exercise.

Exercise increases the expression of brain-derived neurotrophic factor (BDNF) in the brain and contributes to cognitive and sensorimotor functions. This study aimed to elucidate how repeated exercise modifies BDNF expression elicited by a single bout of exercise in the brain using in vivo bioluminescence imaging (BLI). Bdnf-luciferase (Luc) mice with the firefly luciferase gene inserted at the translation start point of the Bdnf gene were used for BLI to monitor changes in BDNF expression in the brain. The treadmill exercise at a speed of 10 m/s for 60 min was repeated 5 days a week for 4 weeks. BLI in individual subjects was repeated four times: before the exercise intervention, on the first exercise day, and 14 and 28 days after the start of the intervention. Each BLI was performed after a single bout of exercise and monitored for 8 h after exercise. Repetitive BLI showed that the exercise regimen enhanced BDNF expression in the brain, specifically at 4-8 h after a single bout of exercise. Repeated exercise for 2 weeks accelerated the start of enhancement after a single bout of exercise, but not after 4 weeks of repeated exercise. This study showed that repeated exercise modulated the time window of exercise-enhanced BDNF expression, suggesting that repeated exercise could change the sensitivity of gene expression to a single bout of exercise. These findings can be attributed to the advantages of in vivo BLI, which allowed us to precisely measure the time course of BDNF expression after repeated exercise in individual subjects.

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.

Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.

Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Its modulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation.

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.

Pharmacological inhibition of histone deacetylases ameliorates cognitive impairment after intracerebral hemorrhage with epigenetic alteration in the hippocampus.

OBJECTIVES: Post-stroke cognitive impairment (PSCI) interferes with neurorehabilitation in patients with stroke. Epigenetic regulation of the hippocampus has been targeted to ameliorate cognitive function. In particular, the acetylation level of histones is modulated by exercise, a potent therapy for patients with stroke. MATERIALS AND METHODS: We examined the effects of exercise and pharmacological inhibition of histone deacetylase (HDAC) using sodium butyrate (NaB) on cognitive function and epigenetic factors in the hippocampus after intracerebral hemorrhage (ICH) to seek beneficial neuronal conditioning against PSCI. Forty rats were randomly assigned to five groups: sham, control, NaB, exercise, and NaB plus exercise groups (n=8 in each group). Except for those in the sham group, all rats underwent stereotaxic ICH surgery with a microinjection of collagenase solution. Intraperitoneal administration of NaB (300 mg/kg) and treadmill exercise (11 m/min for 30 min) were conducted for approximately 4 weeks starting 3 days post-surgery. RESULTS: ICH reduced cognitive function, as detected by the object location test, accompanied by enhanced activity of HDACs. Although exercise did not modulate HDAC activity or cognitive function, repetitive NaB administration increased HDAC activity and ameliorated cognitive impairment induced by ICH. CONCLUSIONS: This study suggests that pharmacological treatment with an HDAC inhibitor could potentially present an enriched epigenetic platform in the hippocampus and ameliorate PSCI for neurorehabilitation following ICH.

Temporal dynamics of brain BDNF expression following a single bout of exercise: A bioluminescence imaging study.

Physical exercise increases brain-derived neurotrophic factor (BDNF) expression in the brain. However, the absence of non-invasive and repetitive monitoring of BDNF expression in the brains of living animals has limited the understanding of how BDNF expression changes after exercise. This study aimed to elucidate the temporal dynamics of BDNF expression in the brain after a single bout of exercise, using in vivo bioluminescence imaging. This study included Bdnf-Luc mice with a firefly Luciferase gene inserted at the translation start site of the mouse Bdnf gene. BDNF expression was evaluated based on the luminescence signal of the luciferase substrate administered to mice. Bioluminescence imaging was performed at 0, 1, 3, 6, 12, and 24 h after treadmill exercise (15 m/min for 1 h). Compared to the sedentary condition of each mouse, the luminescence signal increased by approximately 60 % between 1 and 3 h after exercise. The luminescence signal remained slightly increased by approximately 20 % even 6-24 h after exercise. This study is the first to demonstrate exercise-enhanced BDNF expression in the brains of living animals. These results provide evidence that a single bout of exercise transiently increases BDNF expression in the brain within a limited time window.

Epigenetic modifications in the motor cortex caused by exercise or pharmacological inhibition of histone deacetylases (HDACs) after intracerebral hemorrhage (ICH).

Epigenetic regulation is expected to provide an enriched platform for neurorehabilitation of post-stroke patients. Acetylation of specific lysine residues in histones is a potent epigenetic target essential for transcriptional regulation. Exercise modulates histone acetylation and gene expression in neuroplasticity in the brain. This study sought to examine the effect of epigenetic treatment using a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaB), and exercise on epigenetic markers in the bilateral motor cortex after intracerebral hemorrhage (ICH) to identify a more enriched neuronal condition for neurorehabilitation. Forty-one male Wistar rats were randomly divided into five groups: sham (n = 8), control (n = 9), NaB, exercise (n = 8), and NaB and exercise (n = 8). Intraperitoneal administration of an HDAC inhibitor (300 mg/kg NaB) and treadmill exercise (11 m/min for 30 min) was conducted five days a week for approximately-four weeks. ICH specifically decreased the acetylation level of histone H4 in the ipsilateral cortex, and HDAC inhibition with NaB increased the acetylation level of histone H4 over the sham level, accompanied by an improvement in motor function as assessed by the cylinder test. Exercise increased the acetylation levels of histones (H3 and H4) in the bilateral cortex. Synergistic effects of exercise and NaB were not observed during histone acetylation. Pharmacological treatment with a HDAC inhibitor and exercise can provide an enriched epigenetic platform for neurorehabilitation in an individual manner.

Effect of therapeutic exercise on the balance of patients with progressive supranuclear palsy: A pilot study.

Background: Progressive supranuclear palsy (PSP) is a parkinsonian-like progressive neurodegenerative syndrome. Key clinical features include ocular motor dysfunction, postural instability, and cognitive dysfunction. Maintaining and improving balance function and gait function are very important for patients with PSP with severe postural dysfunction and repeated falls. In addition, patients with PSP have a poor response to pharmacological treatment; hence, rehabilitation is a key approach in dealing with this syndrome. However, no conclusion on the beneficial effects of rehabilitation for patients with PSP have been established in the literature. Objectives: The effectiveness of multiple therapeutic exercise program with probable or possible PSP according to the Movement Disorder Society criteria for the clinical diagnosis of PSP was validated. Methods: Participants underwent multiple therapeutic exercise program customized for each participant, including resistance training, balance training, and walking exercises that were performed for 60-80 minutes a day, 5 days a week for 4 weeks. The outcomes measured were as follows: pull test, Berg Balance Scale (BBS), timed up and go test (TUG), and gait speed test. Results: A total of 117 patients with PSP were enrolled and the analysis was performed on 20 patients with probable PSP. Four-week rehabilitation significantly improved pull test (p = 0.034) and BBS scores (p = 0.001). There were no significant differences both TUG (p = 0.502) and gait speed (p = 0.813). Conclusion: The multiple therapeutic exercise program had beneficial effects on balance performance in patients with PSP in 4 weeks and could be an essential element in their rehabilitation. Although this pilot study was conducted without a control group, it provided valuable information for future prospective randomized controlled trials.

Intracerebral Transplantation of Mesenchymal Stromal Cell Compounded with Recombinant Peptide Scaffold against Chronic Intracerebral Hemorrhage Model.

Background: Due to the lack of effective therapies, stem cell transplantation is an anticipated treatment for chronic intracerebral hemorrhage (ICH), and higher cell survival and engraftment are considered to be the key for recovery. Mesenchymal stromal cells (MSCs) compounded with recombinant human collagen type I scaffolds (CellSaics) have a higher potential for cell survival and engraftment compared with solo-MSCs, and we investigated the validity of intracerebral transplantation of CellSaic in a chronic ICH model. Methods: Rat CellSaics (rCellSaics) were produced by rat bone marrow-derived MSC (rBMSCs). The secretion potential of neurotrophic factors and the cell proliferation rate were compared under oxygen-glucose deprivation (OGD) conditions. rCellSaics, rBMSCs, or saline were transplanted into the hollow cavity of a rat chronic ICH model. Functional and histological analyses were evaluated, and single-photon emission computed tomography for benzodiazepine receptors was performed to monitor sequential changes in neuronal integrity. Furthermore, human CellSaics (hCellSaics) were transplanted into a chronic ICH model in immunodeficient rats. Antibodies neutralizing brain-derived neurotrophic factor (BDNF) were used to elucidate its mode of action. Results: rCellSaics demonstrated a higher secretion potential of trophic factors and showed better cell proliferation in the OGD condition. Animals receiving rCellSaics displayed better neurological recovery, higher intracerebral BDNF, and better cell engraftment; they also showed a tendency for less brain atrophy and higher benzodiazepine receptor preservation. hCellSaics also promoted significant functional recovery, which was reversed by BDNF neutralization. Conclusion: Intracerebral transplantation of CellSaics enabled neurological recovery in a chronic ICH model and may be a good option for clinical application.

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.

Specific inhibition of α5 subunit-containing GABAA receptors enhances locomotor activity and neuronal activity in the motor cortex.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS). This study examined the effect of specific inhibition of α5 subunit-containing GABAA receptors (α5GABAAR) on the behavioral profile and neuronal activity of the CNS using a compound called L-655,708, which is a selective negative allosteric modulator of α5GABAAR. L-655,708 administration significantly increased locomotor activity without anxiety-related behavior. Furthermore, L-655,708 administration significantly increased c-Fos mRNA expression (a neuronal activity marker) in motor area of the cerebral cortex, whereas it hardly altered c-Fos mRNA expression in the sensory cortex, hippocampus, and spinal cord. This study revealed for the first time that alteration of neuronal activity with specific inhibition of α5GABAAR differs depending on each CNS region. α5GABAAR could be a potential target for modulating CNS excitability and behavioral activity.

Skeletal muscle loss and body composition in progressive supranuclear palsy: A retrospective cross-sectional study.

INTRODUCTION: Skeletal muscle mass loss has been associated with decreased physical performance; however, the body composition characteristics in progressive supranuclear palsy (PSP) are not well understood. We investigated body composition parameters, focusing on skeletal muscle mass, in patients with PSP and compared them with those of healthy older adults. METHODS: This retrospective cross-sectional study included 39 patients with PSP and 30 healthy older adults (control group). Using a multi-frequency bioelectrical impedance analysis, we measured the skeletal mass index (SMI), basal metabolism, extracellular water/total body water ratio (ECW/TBW), and body fat percentage and examined the relationship between SMI and age, body mass index (BMI) and other body composition parameters. RESULTS: The PSP group had a higher rate of low muscle mass (56.4%) than the control group (10.0%), although the ages and BMIs were similar. The leg SMI was lower for the PSP group, while the ECW/TBW was higher for the PSP group. The basal metabolism was lower for the PSP group than for the controls but only in the women. The basal metabolism and BMI showed a significant correlation with SMI in the PSP group. There was a significant correlation between SMI and age, ECW/TBW, and body fat percentage in the PSP group but only in the women. CONCLUSION: This study is the first to show that a high proportion of patients with PSP have low muscle mass. We showed differences in terms of sex in muscle mass loss in women with PSP, which was associated with inactivity and aging.

Ipsilateral BDNF mRNA expression in the motor cortex positively correlates with motor function of the affected forelimb after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke that causes major motor impairments. Brain-derived neurotrophic factor (BDNF) is known to have important roles in neuroplasticity and beneficially contributes to stroke recovery. This study aimed to characterize BDNF expression in the motor cortex after ICH and investigate the relationship between cortical BDNF expression and behavioral outcomes using an ICH rat model. Wistar rats were divided into two groups: a SHAM group (n = 7) and an ICH group (n = 8). ICH was induced by the injection of collagenase into the left striatum near the internal capsule. For behavioral assessments, the cylinder test and open field test were performed before surgery and 3 days, 1 week, 2 weeks, and 4 weeks after surgery. Following the behavioral assessments at 4 weeks, BDNF expression in the ipsilateral and contralateral motor cortex was assayed using RT-PCR and ELISA methods. There was no significant difference in either cortical BDNF mRNA or protein expression levels between the SHAM and ICH groups. However, the asymmetry index of BDNF mRNA expression between the ipsilateral and contralateral hemispheres shifted to the ipsilateral hemisphere after ICH. Furthermore, the ipsilateral cortical BDNF mRNA expression level positively correlated with motor function in the affected forelimb after ICH. This study describes for the first time that cortical BDNF mRNA expression is related to post-ICH motor impairment. These results highlight the importance of assessing the interhemispheric laterality of BDNF expression and could help develop novel treatment strategies for BDNF-dependent recovery after ICH.

In vivo local transcranial static magnetic field stimulation alters motor behavior in normal rats.

Transcranial static magnetic field stimulation (tSMS) has inhibitory neuromodulatory effects on the human brain. Most of the studies on static magnetic fields have been performed in vitro. To further understand the biological mechanisms of tSMS, we investigated the effects of in vivo tSMS on motor behavior in normal awake rats. The skull of a male Wistar rat was exposed and a polyethylene tube was attached to the skull using dental cement at the center of the motor cortex (n = 7) or the other cortex (n = 6). By attaching a cylindrical NdFeB neodymium magnet into the tube, in vivo tSMS (REAL) was performed. For SHAM, we applied a similar size non-magnetic stainless-steel cylinder. All rats received twice each SHAM and REAL stimulation every two days using a crossover design, and motor function was measured during the stimulation. Activity level and asymmetry of forelimb use were not affected, but less accurate movements in the horizontal ladder test were found in REAL stimulation of the motor cortex. This study shows that in vivo tSMS has inhibitory neuromodulatory effects on motor behavior depending on the stimulated region on the rat cortex.

Transcranial static magnetic stimulation over the motor cortex can facilitate the contralateral cortical excitability in human.

Transcranial static magnetic stimulation (tSMS) has been focused as a new non-invasive brain stimulation, which can suppress the human cortical excitability just below the magnet. However, the non-regional effects of tSMS via brain network have been rarely studied so far. We investigated whether tSMS over the left primary motor cortex (M1) can facilitate the right M1 in healthy subjects, based on the hypothesis that the functional suppression of M1 can cause the paradoxical functional facilitation of the contralateral M1 via the reduction of interhemispheric inhibition (IHI) between the bilateral M1. This study was double-blind crossover trial. We measured the corticospinal excitability in both M1 and IHI from the left to right M1 by recording motor evoked potentials from first dorsal interosseous muscles using single-pulse and paired-pulse transcranial magnetic stimulation before and after the tSMS intervention for 30 min. We found that the corticospinal excitability of the left M1 decreased, while that of the right M1 increased after tSMS. Moreover, the evaluation of IHI revealed the reduced inhibition from the left to the right M1. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of tSMS in human.

Effects of simulated peripheral visual field loss on the static postural control in young healthy adults.

BACKGROUND: Integration of visual, vestibular, and proprioceptive sensations contributes to postural control. People with peripheral visual field loss have serious postural instability. However, the directional specificity of postural stability and sensory reweighting caused by gradual peripheral visual field loss remain unclear. RESEARCH QUESTION: What are the effects of peripheral visual field loss on static postural control? METHODS: Fifteen healthy young adults participated in this study. The participants were asked to stand quietly on a foam surface. Three conditions of virtual visual field loss (90°, 45°, and 15°) were provided by a head-mounted display, and ground reaction forces were collected using a force plate to calculate the displacements of the center of pressure (COP). RESULTS: The root mean square (RMS), mean velocity, and 95% ellipse area of COP displacements in the horizontal plane increased, and RMS in the anteroposterior (AP) direction was unchanged under the smallest visual field condition compared to the largest one. The power spectrum density of COP displacements in the low-frequency band was decreased and that in the medium-frequency band was increased in the AP direction. SIGNIFICANCE: During quiet standing of young healthy adults with peripheral visual field loss, increased peripheral visual field loss resulted in lower postural stability. Postural stability in the AP direction was maintained contrary to the functional sensitivity hypothesis. Peripheral visual field loss reduced the weighting of the visual input and increased that of the vestibular input in the AP direction to maintain equilibrium.

Exercise and pharmacological inhibition of histone deacetylase improves cognitive function accompanied by an increase of gene expressions crucial for neuronal plasticity in the hippocampus.

Exercise is recognized to increase the expression of neurotrophic genes in the hippocampus and prevent cognitive impairment. Histone deacetylase (HDAC) inhibitor acetylate histones and enhance gene transcription in epigenetic regulation. HDAC inhibitors are expected to be an efficacious pharmacological treatment for cognitive function. This study aimed to examine the effect of HDAC inhibitors and exercise on epigenetic markers and neurotrophic gene expression in the hippocampus to find a more enriched brain conditioning for cognitive function based on the synergic effects of pharmacological treatment and behavioral therapy. Thirteen-week-old male mice were divided into four groups. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately 10 m/min for 60 min) were performed 5 days a week for 4 weeks. NaB administration increased the expression of an immediate-early gene, a neurotrophin, and a neurotrophin receptor in the hippocampus. These results indicate that HDAC inhibition could present an enriched platform for neuronal plasticity in the hippocampus and cognitive function. The novel object recognition test showed that NaB administration increased the score. Notably, the step-through passive avoidance test showed improved learning and memory in the presence of exercise and exercise, indicating that the mice acquired fear memory, specifically in the presence of NaB administration plus exercise. This study found that repetitive administration of HDAC inhibitors improved cognitive function and HDAC inhibitor administration plus exercise has a synergic effect on learning and memory, accompanying the enhancement of crucial gene transcriptions for neuronal plasticity in the hippocampus.

Effects of exercise and pharmacological inhibition of histone deacetylases (HDACs) on epigenetic regulations and gene expressions crucial for neuronal plasticity in the motor cortex.

The objective of this study was to examine the effect of epigenetic treatment using an histone deacetylases (HDAC) inhibitor in addition to aerobic exercise on the epigenetic markers and neurotrophic gene expressions in the motor cortex, to find a more enriched brain pre-conditioning for motor learning in neurorehabilitation. ICR mice were divided into four groups based on two factors: HDAC inhibition and exercise. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately at 10 m/min for 60 min) were conducted five days a week for four weeks. NaB administration inhibited total HDAC activity and enhanced acetylation level of histones specifically in histone H4, accompanying the increase of transcription levels of immediate-early genes (IEGs) (c-fos and Arc) and neurotrophins (BDNF and NT-4) crucial for neuroplasticity in the motor cortex. However, exercise enhanced HDAC activity and acetylation level of histone H4 and H3 without the modification of transcription levels. In addition, there were no synergic effects between HDAC inhibition and the exercise regime on the gene expressions. This study showed that HDAC inhibition could present more enriched condition for neuroplasticity to the motor cortex. However, exercise-induced neurotrophic gene expressions could depend on exercise regimen based on the intensity, the term etc. Therefore, this study has a novelty suggesting that pharmacological HDAC inhibition could be an alternative potent approach to present a neuronal platform with enriched neuroplasticity for motor learning and motor recovery, however, an appropriate exercise regimen is expected in this approach.

Low-Level Inhibition of GABAergic Synapses Enhances Gene Expressions Crucial for Neuronal Plasticity in the Hippocampus After Ischemic Stroke.

OBJECTIVE: Pharmacological inhibition of GABAergic synapses could represent a potent neuromodulation strategy to activate hippocampal neurons and increase neurotrophic factor gene expression, thus exerting a beneficial effect on post-stroke cognitive impairment (PSCI). The objective of this study was to assess the effects of low-level inhibition of GABAergic synapses on hippocampal gene expressions related to neuroplasticity using the middle cerebral artery occlusion surgery (MCAO) ischemic stroke rat model. METHODS: The animals were randomly assigned to three experimental groups-(1) a sham operated group (SHAM), (2) a control group (CON), and (3) a bicuculline group (BIC). MCAO was performed in the CON and BIC groups. A non-epileptic dose of bicuculline (0.25 mg/kg) was intraperitoneally administered every day for two weeks, starting three days after surgery, to the rats in the BIC group. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), in relation to neurotrophic intracellular signal, p75, in relation to apoptosis, and synaptophysin (SYP) and PSD-95, synaptic markers, were assessed in the hippocampus ipsilateral to the ischemic site. RESULTS: MCAO increased the gene expression of TrkB. Furthermore, MCAO plus bicuculline administration increased the expression ratio of TrkB to p75 and SYP gene expression. CONCLUSION: Therefore, this study showed that administration of bicuculline after stroke beneficially modulated the expression of crucial genes for neuroplasticity, including BDNF receptors and SYP, in the ipsilateral hippocampus, suggesting that low-level inhibition of GABAergic synapses could lead to beneficial neuromodulation in the hippocampus after stroke.

Exercise Plus Pharmacological Neuromodulation of Synaptic Inhibition Enhance Motor Function Recovery After Ischemic Stroke.

The objective of this study was to examine the interactive effects of exercise and low-level inhibition of GABAA receptors on the recovery of motor function and BDNF expression in the primary motor cortex (M1) of a stroke rat model. Male Sprague-Dawley rats were divided into five groups: sham (SHAM), control (CON), exercise (EX), bicuculline (BIC), and bicuculline plus exercise (BICEX) groups. All rats, except those in the SHAM group, underwent middle cerebral artery occlusion (MCAO) surgery to induce an ischemic stroke. GABAA receptor antagonist, bicuculline (0.25 mg/kg, i.p.), was administered to the BIC and BICEX groups. The EX and BICEX groups exercised on a treadmill (11 m/min for 30 min). Each intervention started 3 days after the MCAO surgery and was carried out every day for 2 weeks. Following the intervention, bilateral M1 BDNF mRNA and protein expression levels were assessed using qRT-PCR and ELISA. Marginal recovery was found in the EX and BIC groups, whereas motor function recovery was enhanced with exercise in the presence of BIC administration specifically in the BICEX group. Furthermore, BDNF protein level in the ipsilateral M1 was significantly higher in the BICEX group than in other groups. This study indicated that exercise combined with low-level inhibition of GABAA receptors after stroke could facilitate the recovery of motor function accompanied by BDNF upregulation in the ipsilateral M1. Therefore, this study provides a novel insight of pharmacological neuromodulation into stroke rehabilitation.