The Role of Purinergic Signaling in the Pathophysiology of Perinatal Hypoxic-Ischemic Encephalopathy

Perinatal hypoxic-ischemic encephalopathy (HIE), known as birth asphyxia, remains a major contributor to poor neurodevelopmental outcomes including cerebral palsy and seizures. One striking feature of HIE injury is a delayed progression of neuronal degeneration that spreads over time from the most severely damaged areas outward into neighboring undamaged regions. There is increasing evidence that these lesions act as sites of origin for waves of spreading depression (SD), a wave of neuronal and glial depolarization, that progressively enlarge the brain lesions. While the pathophysiology of SD is still under debate, there is increasing evidence that purinergic receptors in conjunction with connexin and pannexin 1 channels are necessary for sustained propagation of the waves and neuroinflammation. This review intends to discuss the relative contribution of purinergic signaling and connexin and pannexin 1 channels to trigger and spread SD waves leading to the development of progressive brain lesions under conditions of perinatal HIE

Nanotechnology in the diagnosis and treatment of stroke

•Nanotechnology has not only opened a new window for the delivery of drugs for stroke therapy but also has improved and eased stroke diagnosis.•Nanoparticles made from gold, iron oxide, perfluorocarbon, polymers and quantum dots may be robustly employed for stroke diagnosis and therapy.•Biocompatibility and safety concerns of nanoparticles may be overcome and enhanced by structural modification or by coating. Increasing developments in the field of nanotechnology have ignited its use in stroke diagnosis and treatment. The benefits of structural modification, ease of synthesis, and biocompatibility support the use of nanomaterials in the clinic. The pathophysiology of stroke is complex, involving different brain regions; hence, therapeutic agents are required to be delivered to specific regions. Nanoparticles (NPs) can be engineered to help improve the delivery and release of therapeutic agents in a localized manner, especially in the penumbra. This contributes not only to therapy, but also to neurosurgery and neuroimaging. Nanomaterials also offer high efficacy with few adverse effects. In this review, we provide a concise summary of the caveats associated with nanotechnology with respect to stroke therapy and diagnosis. The growing field of nanotechnology offers an exciting prospect for research into diagnostics and interventions for stroke. Their limited adverse effects along with high efficacy make nanotechnologies highly sought-after as promising therapeutic modalities

Endovascular Stem Cell Therapy Post Stroke Rescues Neurons from Endoplasmic Reticulum Stress-Induced Apoptosis by Modulating Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling

Ischemic stroke is devastating, with serious long-term disabilities affecting millions of people worldwide. Growing evidence has shown that mesenchymal stem cells (MSCs) administration after stroke provides neuroprotection and enhances the quality of life in stroke patients. Previous studies from our lab have shown that 1 × 105 MSCs administered intra-arterially (IA) at 6 h post stroke provide neuroprotection through the modulation of inflammasome and calcineurin signaling. Ischemic stroke induces endoplasmic reticulum (ER) stress, which exacerbates the pathology. The current study intends to understand the involvement of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling in preventing apoptosis induced by ER stress post stroke following IA MSCs administration. Ischemic stroke was induced in ovariectomized female Sprague Dawley rats. The MSCs were administered IA, and animals were sacrificed at 24 h post stroke. Infarct area, neurological deficit score, motor coordination, and biochemical parameters were evaluated. The expression of various genes and proteins was assessed. An inhibition study was also carried out to confirm the involvement of BDNF/TrkB signaling in ER stress-induced apoptosis. IA-administered MSCs improved functional outcomes, reduced infarct area, increased neuronal survival, and normalized biochemical parameters. mRNA and protein expression of ER stress markers were reduced, while those of BDNF and TrkB were increased. Reduction in ER stress-mediated apoptosis was also observed. The present study shows that IA MSCs administration post stroke provides neuroprotection and can modulate ER stress-mediated apoptosis via the BDNF/TrkB signaling pathway

A Friend or Foe: Calcineurin across the Gamut of Neurological Disorders

The serine/threonine phosphatase calcineurin (CaN) is a unique but confounding calcium/calmodulin-mediated enzyme. CaN has shown to play essential roles from regulating calcium homeostasis to being an intricate part of learning and memory formation. Neurological disorders, despite differing in their etiology, share similar pathological outcomes, such as mitochondrial dysfunction and apoptotic signaling brought about by excitotoxic elements. CaN, being deeply integrated in vital neuronal functions, may be implicated in various neurological disorders. Understanding the enzyme and its physiological niche in the nervous system is vital in uncovering its roles in the spectrum of brain disorders. By reviewing the crosstalk in different neurological pathologies, a possible grasp of CaN’s complex signaling may lead to forming better neurotherapy. This Outlook attempts to explore the various neuronal functions of CaN and investigate its pervasive role through the gamut of neurological disorders. Calcineurin has vital biological functions with significant roles across different neuropathies. Herein, we present its involvement under varying neuropathological conditions

Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke

Stroke results in long term serious disability that affect millions across the globe. Several clinical and preclinical studies have reinforced the therapeutic use of stem cells in stroke patients to enhance their quality of life. Previous studies from our lab have demonstrated that 1*10 allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) when given intraarterially (IA) render neuroprotection by modulating the expression of inflammasomes. Sirtuins are a class of important deacylases having a significant role in cellular functioning. Sirtuin-1 (SIRT-1) is an important enzyme essential for regulating cellular metabolism, which is reduced following an ischemic episode. The present study aims to unviel the role of MSCs in regulating the brain SIRT-1 levels following stroke and the involvement of SIRT-1 in regulating inflammasome signaling to reduce cellular apoptosis towards rendering neuroprotection. 6 h post-reversible middle cerebral artery occlusion (MCAo), ovariectomized Sprague Dawley (SD) rats were infused intraarterially with 1*10 MSCs. 24 h after MCAo animals were examined for functional and behavioral outcomes. Brains were collected for assessing size of infarct and neuronal morphology. Molecular and immunofluroscence studies were also performed for assessing changes in gene and protein expressions. Extent of apoptosis was also determined in different groups. Inhibition study with SIRT-1 specific inhibitor EX-527 was also performed. A reduction in infarct size and improvement in motor functional and behavioral outcomes following infusion of MSCs IA at 6 h post-stroke was observed. Increase in average neuronal density and neuronal length was also seen. Increased expression of SIRT-1, BDNF and concomitant reduction in the expression of different inflammatory and apoptotic markers in the brain cortical regions were observed following MSCs treatment. Our study provides a preliminary evidence that post-stroke IA MSCs therapy regulates SIRT-1 to modulate NF-κB pathway to mitigate inflammasome signaling and cellular apoptosis. This study using IA approach for administering MSCs is highly relevant clinically. Our study is the first to report that neuroprotective effects of IA MSCs in rodent focal ischemia is mediated by SIRT-1 regulation of inflammasome signaling