Inflammation-relevant microbiome signature of the stroke brain, gut, spleen, and thymus and the impact of exercise.

Stroke remains a significant unmet need in the clinic with few therapeutic options. We, and others, have implicated the role of inflammatory microbiota in stroke secondary cell death. Elucidating this inflammation microbiome as a biomarker may improve stroke diagnosis and treatment. Here, adult Sprague-Dawley rats performed 30 minutes of exercise on a motorized treadmill for 3 consecutive days prior to transient middle cerebral artery occlusion (MCAO). Stroke animals that underwent exercise showed 1) robust behavioral improvements, 2) significantly smaller infarct sizes and increased peri-infarct cell survival and 3) decreasing trends of inflammatory microbiota BAC303, EREC482, and LAB158 coupled with significantly reduced levels of inflammatory markers ionized calcium binding adaptor molecule 1, tumor necrosis factor alpha, and mouse monoclonal MHC Class II RT1B in the brain, gut, spleen, and thymus compared to non-exercised stroke rats. These results suggest that a specific set of inflammatory microbiota exists in central and peripheral organs and can serve as a disease biomarker and a therapeutic target for stroke.

Progress in progestin-based therapies for neurological disorders.

Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury.

Ischemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long-term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM-MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM-MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell-based combination treatments.

Fast-tracking regenerative medicine for traumatic brain injury.

Traumatic brain injury remains a global health crisis that spans all demographics, yet there exist limited treatment options that may effectively curtail its lingering symptoms. Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death. Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect. In this review, we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation, edema, and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants. Although these studies of stand-alone treatments have yielded some positive results, more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy. Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts. The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.

Harnessing the anti-inflammatory properties of stem cells for transplant therapy in hemorrhagic stroke.

Hemorrhagic stroke is a global health crisis plagued by neuroinflammation in the acute and chronic phases. Neuroinflammation approximates secondary cell death, which in turn robustly contributes to stroke pathology. Both the physiological and behavioral symptoms of stroke correlate with various inflammatory responses in animal and human studies. That slowing the secondary cell death mediated by this inflammation may attenuate stroke pathology presents a novel treatment strategy. To this end, experimental therapies employing stem cell transplants support their potential for neuroprotection and neuroregeneration after hemorrhagic stroke. In this review, we evaluate experiments using different types of stem cell transplants as treatments for stroke-induced neuroinflammation. We also update this emerging area by examining recent preclinical and clinical trials that have deployed these therapies. While further investigations are warranted to solidify their therapeutic profile, the reviewed studies largely posit stem cells as safe and potent biologics for stroke, specifically owing to their mode of action for sequestering neuroinflammation and promoting neuroregenerative processes.

Stroke gets in your eyes: stroke-induced retinal ischemia and the potential of stem cell therapy.

Stroke persists as a global health and economic crisis, yet only two interventions to reduce stroke-induced brain injury exist. In the clinic, many patients who experience an ischemic stroke often further suffer from retinal ischemia, which can inhibit their ability to make a functional recovery and may diminish their overall quality of life. Despite this, no treatments for retinal ischemia have been developed. In both cases, ischemia-induced mitochondrial dysfunction initiates a cell loss cascade and inhibits endogenous brain repair. Stem cells have the ability to transfer healthy and functional mitochondria not only ischemic neurons, but also to similarly endangered retinal cells, replacing their defective mitochondria and thereby reducing cell death. In this review, we encapsulate and assess the relationship between cerebral and retinal ischemia, recent preclinical advancements made using in vitro and in vivo retinal ischemia models, the role of mitochondrial dysfunction in retinal ischemia pathology, and the therapeutic potential of stem cell-mediated mitochondrial transfer. Furthermore, we discuss the pitfalls in classic rodent functional assessments and the potential advantages of laser Doppler as a metric of stroke progression. The studies evaluated in this review highlight stem cell-derived mitochondrial transfer as a novel therapeutic approach to both retinal ischemia and stroke. Furthermore, we posit the immense correlation between cerebral and retinal ischemia as an underserved area of study, warranting exploration with the aim of these treating injuries together.