Striatal Stimulation Nurtures Endogenous Neurogenesis and Angiogenesis in Chronic-Phase Ischemic Stroke Rats

Morimoto, T; Yasuhara, Takao; Kameda, Masahiro; Baba, Tetsuya; Kuramoto, Satoshi; Kondo, Akihiko; Takahashi, Kazuya; Tajiri, Naoki; Wang, Feifei; Meng, Jing; Ji, Yuan; Kadota, Toshikazu; Maruo, Tomoko; Kinugasa, Kazushi; Miyoshi, Yasuyuki; Shingo, Tetsuro; Borlongan, Cesario V.; Date, Isao

doi:10.3727/096368910x544915

Cited by 43 publications

(31 citation statements)

References 77 publications

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“…Similar reports have demonstrated cross‐talk between secreted factors (e.g., apoptosis, inflammation, oxidative stress) (; Brill et al, 2009; Chapman et al, 2015; Lu, Jones, Snyder, & Tuszynski, 2003; Zhang et al, 2015) and neurogenesis following brain insults, including stroke (Kernie and Parent, 2010; Yamashita et al, 2006). We (Hara et al, 2007; Morimoto et al, 2011; Tajiri et al, 2013), and others, have shown the important contribution of neurogenic factors in stroke brain remodeling (Jablonska et al, 2016; Rosell et al, 2013; Seo et al, 2014; Venna, Xu, Doran, Patrizz, & McCullough, 2014). Altogether, these results allude to host neurogenesis and its secreted neurogenic factors as key therapeutic targets of NSI‐189 in affording behavioral and neurostructural benefits in stroke.…”

Section: Discussionmentioning

confidence: 87%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI‐189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti‐depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, 2016, ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI‐189 in adult Sprague–Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke‐induced motor and neurological deficits, which was maintained up to 24 weeks post‐stroke. Histopathological assessment of stroke brains from NSI‐189‐treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI‐189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI‐189 treatment characterized by significant attenuation of OGD/R‐mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI‐189 as a therapeutic agent well beyond the initial 6‐hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

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Section: Discussionmentioning

confidence: 87%

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Tajiri

Quach

Kaneko

et al. 2017

Journal Cellular Physiology

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“…This suggests that electrical stimulation increased the expression of SDF-1α a few days after ischemic stroke. While electrical simulation enhances expression of various cytokines like a vascular endothelial growth factor (VEGF), Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) [18, 41], there are no reports about the effect of electrostimulation on expression of SDF-1α in the brain. Interestingly, the expression of SDF-1α was significantly increased in the anal sphincter of rats immediately after 1 hour of electrical simulation [42].…”

Section: Discussionmentioning

confidence: 99%

Electrical Stimulation Enhances Migratory Ability of Transplanted Bone Marrow Stromal Cells in a Rodent Ischemic Stroke Model

Morimoto

Yasuhara

Kameda

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone marrow stromal cells (BMSCs) transplantation is an important strategy for the treatment of ischemic stroke. Currently, there are no effective methods to guide BMSCs toward the targeted site. In this study, we investigated the effect of electrical stimulation on BMSCs migration in an ischemic model of rats. Methods: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. BMSCs (2.5×10⁵ cells/ 4 µl PBS) were stereotaxically injected into the left corpus callosum at 1 day after MCAO. After BMSCs injection, a plate electrode with a diameter of 3 mm connected to an implantable electrical stimulator was placed on the right frontal epidural space and a counter electrode was placed in the extra-cranial space. Electrical stimulation at preset current (100 µA) and frequency (100 Hz) was performed for two weeks. Behavioral tests were performed at 1, 4, 8, and 15 days after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at 15 days after MCAO for evaluation of infarction area and the migration distance and area of BMSCs found in the brain tissue. After evaluating cell migration, we proceeded to explore the mechanisms guiding these observations. MCAO rats without BMSCs transplantation were stimulated with same current and frequency. At 1 and 2 weeks after MCAO, rats were euthanized to evaluate stromal cell-derived factor 1 alpha (SDF-1α) level of brain tissues in the bilateral cortex and striatum. Results: Behavioral tests at 4, 8, and 15 days after MCAO revealed that stimulation group displayed significant amelioration in mNSS and cylinder test compared to control group (p<0.05). Similarly, the infarction areas of stroke rats in stimulation group were significantly decreased compared to control group (p<0.05). Migration distance and area of transplanted BMSCs were significantly longer and wider respectively in stimulation group. An increased concentration gradient of SDF-1α in stimulation group accompanied this enhanced migration of transplanted cells. Conclusions: These results suggest that electrical stimulation enhances migratory ability of transplanted BMSCs in ischemic stroke model of rats. If we can direct the implanted BMSCs to the site of interest, it may lead to a greater therapeutic effect.

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“…Striatal stimulation also offers neuroprotection in cerebral ischemia, but via alternate mechanisms involving neural repair. Striatal stimulation enhances migration of neural progenitor cells towards the penumbra and their subsequent differentiation into neurons [80]. In acute models, cortical stimulation may operate by upregulating neurotrophic and angiogenic factors in tandem with suppression of apoptotic cell death [81].…”

Section: Differentiating Between Short-and Long-term Mechanisms Of Comentioning

confidence: 99%

Invasive Neurostimulation in Stroke Rehabilitation

Plow

Machado

2014

Neurotherapeutics

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The last decade has seen a growing interest in adjuvant treatments that synergistically influence mechanisms underlying rehabilitation of paretic upper limb in stroke. One such approach is invasive neurostimulation of spared cortices at the periphery of a lesion. Studies in animals have shown that during training of paretic limb, adjuvant stimulation targeting the peri-infarct circuitry enhances mechanisms of its reorganization, generating functional advantage. Success of early animal studies and clinical reports, however, failed to translate to a phase III clinical trial. As lesions in humans are diffuse, unlike many animal models, peri-infarct circuitry may not be a feasible, or consistent target across most. Instead, alternate mechanisms, such as changing transcallosal inhibition between hemispheres, or reorganization of other viable regions in motor control, may hold greater potential. Here, we review comprehensive mechanisms of clinical recovery and factors that govern which mechanism(s) become operative when. We suggest novel approaches that take into account a patient's initial clinical-functional state, and findings from neuroimaging and neurophysiology to guide to their most suitable mechanism for ideal targeting. Further, we suggest new localization schemes, and bypass strategies that indirectly target peri-lesional circuitry, and methods that serve to counter technical and theoretical challenge in identifying and stimulating such targets at the periphery of infarcts in humans. Last, we describe how stimulation may modulate mechanisms differentially across varying phases of recovery-a temporal effect that may explain missed advantage in clinical trials and help plan for the next stage. With information presented here, future trials would effectively be able to target patient's specific mechanism(s) with invasive (or noninvasive) neurostimulation for the greatest, most consistent benefit. [2], which remains one of the most important predictors of disability and poor quality of life [3]. Disability adds to the costs of disease management that total $74 billion/ year [4]. Developing methods to effectively alleviate residual deficits will reduce health and economic burden of stroke.Several evidence-based rehabilitative approaches have been developed with prominent ones, including neuromuscular electrical stimulation [5], motor learning [6], robotic training [7] constraint-induced movement therapy [8], and bilateral arm training [9], etc. In spite of extensive therapy, recovery is frequently incomplete [10]. There is a critical need for adjuvant strategies that augment rehabilitative outcomes of paretic hand.The last decade has seen a growing interest in the promise of adjuvant treatments that synergistically influence mechanisms associated with rehabilitation. One such approach is invasive neuromodulation, involving electrical stimulation applied to cortical or subcortical targets spared by stroke. By directly stimulating viable targets, it is believed that potential for plasticity underlying reh...

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Striatal Stimulation Nurtures Endogenous Neurogenesis and Angiogenesis in Chronic-Phase Ischemic Stroke Rats

Cited by 43 publications

References 77 publications

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

Electrical Stimulation Enhances Migratory Ability of Transplanted Bone Marrow Stromal Cells in a Rodent Ischemic Stroke Model

Invasive Neurostimulation in Stroke Rehabilitation

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