Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke.

Aquaporins (AQPs) are a family of transmembrane water channels expressed in all living organisms. AQPs facilitate osmotically driven water flux across biological membranes and, in some cases, the movement of small molecules (such as glycerol, urea, CO2, NH3, H2O2). Protein–protein interactions play essential roles in protein regulation and function. This review provides a comprehensive overview of the current knowledge of the AQP interactomes and addresses the molecular basis and functional significance of these protein–protein interactions in health and diseases. Targeting AQP interactomes may offer new therapeutic avenues as targeting individual AQPs remains challenging despite intense efforts.

https://www.mdpi.com/1422-0067/23/17/9615/pdf?version=1661410025

Insight into the Mammalian Aquaporin Interactome

Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions, including chronic pain. Astrocytes regulate nociceptive synaptic transmission and network function via neuron-glia and glia-glia interactions to exaggerate pain signals under chronic pain conditions. It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Therefore, this review presents our current understanding of the roles of astrocytes in chronic pain, how they regulate nociceptive responses, and their cellular and molecular mechanisms of action. 

/pdf/astrocytes-in-chronic-pain-cellular-and-molecular-mechanisms-2ndl4g2k.pdf

Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms

Ischemic stroke is associated with increasing morbidity and has become the main cause of death and disability worldwide. Cerebral edema is a serious complication arising from ischemic stroke. It causes an increase in intracranial pressure, rapid deterioration of neurological symptoms, and formation of cerebral hernia, and is an important risk factor for adverse outcomes after stroke. To date, the detailed mechanism of cerebral edema after stroke remains unclear. This limits advances in prevention and treatment strategies as well as drug development. This review discusses the classification and pathological characteristics of cerebral edema, the possible relationship of the development of cerebral edema after ischemic stroke with aquaporin 4, the SUR1-TRPM4 channel, matrix metalloproteinase 9, microRNA, cerebral venous reflux, inflammatory reactions, and cerebral ischemia/reperfusion injury. It also summarizes research on new therapeutic drugs for post-stroke cerebral edema. Thus, this review provides a reference for further studies and for clinical treatment of cerebral edema after ischemic stroke.

/pdf/cerebral-edema-after-ischemic-stroke-pathophysiology-and-2pe59pf1.pdf

Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms

In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP‐ channel function, sulfonylureas improve long‐term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo‐motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8‐related neonatal‐onset diabetes mellitus.

Sulfonylurea for improving neurological features in neonatal diabetes: A systematic review and meta‐analyses

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials.

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review.

INTRODUCTION Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.

Sudhanshu P. Raikwar

Papers

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review.

Emerging therapeutic targets for cerebral edema.