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Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood‐brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment. [ABSTRACT FROM AUTHOR]

Summary: Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro‐inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized. [ABSTRACT FROM AUTHOR]

Aims: Exposure to recurrent hypoglycemia (RH) is common in diabetic patients receiving glucose‐lowering therapies and is implicated in causing cognitive impairments. Despite the significant effect of RH on hippocampal function, the underlying mechanisms are currently unknown. Our goal was to determine the effect of RH exposure on hippocampal metabolism in treated streptozotocin‐diabetic rats. Methods: Hyperglycemia was corrected by insulin pellet implantation. Insulin‐treated diabetic (ITD) rats were exposed to mild/moderate RH once a day for 5 consecutive days. Results: The effect of RH on hippocampal metabolism revealed 65 significantly altered metabolites in the RH group compared with controls. Several significant differences in metabolite levels belonging to major pathways (eg, Krebs cycle, gluconeogenesis, and amino acid metabolism) were discovered in RH‐exposed ITD rats when compared to a control group. Key glycolytic enzymes including hexokinase, phosphofructokinase, and pyruvate kinase were affected by RH exposure. Conclusion: Our results demonstrate that the exposure to RH leads to metabolomics alterations in the hippocampus of insulin‐treated streptozotocin‐diabetic rats. Understanding how RH affects hippocampal metabolism may help attenuate the adverse effects of RH on hippocampal functions. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) and mitochondria are fundamental organelles highly interconnected with a specialized set of proteins in cells. ER–mitochondrial interconnections form specific microdomains, called mitochondria‐associated ER membranes, that have been found to play important roles in calcium signaling and lipid homeostasis, and more recently in mitochondrial dynamics, inflammation, and autophagy. It is not surprising that perturbations in ER–mitochondria connections can result in the progression of disease, especially neurological disorders; hence, their architecture and regulation are crucial in determining the fate of cells and disease. The molecular identity of the specialized proteins regulating ER–mitochondrial crosstalk remains unclear. Our discussion here describes the physical and functional crosstalk between these two dynamic organelles and emphasizes the outcome of altered ER–mitochondrial interconnections in neurological disorders. [ABSTRACT FROM AUTHOR]

In the treatment of both type 1 and type 2 diabetes mellitus, maintaining a euglycemic state represents one of the key challenges. Improper dosing and administration of glucose‐lowering drugs is associated with an increased risk of recurrent hypoglycemia episodes. In addition, the risk of adverse cardiovascular events in diabetic patients, particularly myocardial infarctions and strokes, is well established. Current research indicates a potential link between the baseline risk of cardio/cerebrovascular events in diabetic patients and exposure to hypoglycemia. In this review of the literature, we aim to determine if a relationship exists between recurrent hypoglycemia and adverse neurovascular events. Chronic hyperglycemia in diabetic patients can lead to a variety of long‐term complications. Of particular importance is an increased risk of cardiovascular diseases, which is reported as the leading cause of death in diabetic patients. In this review of the literature, we aim to determine if a relationship exists between recurrent hypoglycemia and adverse neurovascular events. [ABSTRACT FROM AUTHOR]

Stroke is devastating and a major cause of morbidity and mortality around the world. The innate immune response plays an important role in various brain injuries, including stroke, and targeting it for therapeutic interventions would likely prove beneficial. The panoply of inflammatory cells, which induce various cellular, hormonal, and biochemical alterations, mediates the rapid progression of injury in stroke. The inflammasome, a multiprotein oligomer and a key component of specific innate immune responses, contributes toward the worsening of stroke outcomes by activating inflammatory cytokines. Acidotoxicity, mediated by acid‐sensing ion channels (ASICs), also contributes toward exacerbating the condition. A role for ASICs in stroke, through the activation of the inflammasome, is emerging, which opens new avenues for understanding and intervening in stroke. In this review, we describe the various types of inflammasomes and their mechanisms of activation in stroke. Furthermore, therapeutic approaches targeting the inflammasome and that may be helpful in improving stroke outcome are discussed. Schematic diagram representing the various mechanisms involved in activation of inflammasomes. Lack of oxygen to brain cells in stroke leads to a reduction in aerobic respiration that further decreases the ATP/AMP ratio and as a result the NLRP1 inflammasome is activated in an AMPK‐dependent manner. Oxygen deprivation also causes the cells to undergo anaerobic glycolysis resulting in accumulation of lactic acid. Lactic acid lowers the pH, which stimulates ASIC1a and leads to activation of the BK channel and then increased efflux of potassium ions. The decrease in intracellular potassium ions leads to the activation of the NLRP1 inflammasome. ATP depletion leads to conversion of the inactive ATP‐bound inflammasome into the active ADP‐bound inflammasome. Lysosomes release cathepsins that trigger the activation of inflammasomes. ROS released by mitochondria directly activate NLRP1 and NLRP3 inflammasomes. [ABSTRACT FROM AUTHOR]

Abstract: Stroke is devastating and a major cause of morbidity and mortality around globe. Current interventions for ischemic stroke include thrombolytics, clot retrieval devices and/or intravenous tissue plasminogen activators (tPA), the latter two becoming the first line of treatment. Owing to the limitations of tPA to elicit therapeutic benefits in a narrow time window, new pharmacological interventions are needed. Exploring noncoding RNAs (ncRNAs) may be a promising option for stroke treatment. ncRNAs are endogenous molecules that play key roles in the pathophysiology of many functions and diseases, including during ischemic stroke. Small ncRNAs such as microRNAs, Piwi‐interacting RNAs, and long ncRNAs affect the genetic machinery at molecular levels. These small ncRNAs, along with their target genes and RNA transcripts, are involved in repair and recovery mechanisms after stroke. The potential of ncRNAs to regulate physiological processes highlights their potential therapeutic importance. Here, we enumerate the details and roles of different types of ncRNAs as biomarkers and targets for future stroke intervention. [ABSTRACT FROM AUTHOR]

Numerous preclinical studies have been carried out using mesenchymal stem cells (MSCs) therapy for ischemic stroke. The purpose of the present meta‐analysis is to review the quality of preclinical studies. In all, 4,361 articles were identified, out of which 64 studies were included (excluding in vitro studies). The results were obtained across species, route, and time of administration, immunogenicity, and doses. The median quality score 4.90/10, confidence interval 95%, and large effect size were observed, which strongly supports the translation potential of MSC therapy for ischemic stroke. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 121, 157-167. Abstract Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-β) in female rats compared with exposure to nicotine alone. Mitochondrial ER-β regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-β and its function could help delineate the harmful synergism between nicotine and OC. In this study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-β alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-β protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared with saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared with the nicotine or saline groups. Similarly, the silencing of ER-β reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-β loss is responsible for mitochondrial malfunction after NOC. [ABSTRACT FROM AUTHOR]

During the pre-hibernation season, arctic ground squirrels (AGS) can tolerate 8 min of asphyxial cardiac arrest (CA) without detectable brain pathology. Better understanding of the mechanisms regulating innate ischemia tolerance in AGS has the potential to facilitate the development of novel prophylactic agents to induce ischemic tolerance in patients at risk of stroke or CA. We hypothesized that neuroprotection in AGS involves robust maintenance of ion homeostasis similar to anoxia-tolerant turtles. Ion homeostasis was assessed by monitoring ischemic depolarization (ID) in cerebral cortex during CA in vivo and during oxygen glucose deprivation in vitro in acutely prepared hippocampal slices. In both models, the onset of ID was significantly delayed in AGS compared with rats. The epsilon protein kinase C (εPKC) is a key mediator of neuroprotection and inhibits both Na+/K+-ATPase and voltage-gated sodium channels, primary mediators of the collapse of ion homeostasis during ischemia. The selective peptide inhibitor of εPKC (εV1-2) shortened the time to ID in brain slices from AGS but not in rats despite evidence that εV1-2 decreased activation of εPKC in brain slices from both rats and AGS. These results support the hypothesis that εPKC activation delays the collapse of ion homeostasis during ischemia in AGS. [ABSTRACT FROM AUTHOR]