Drug development in targeting ion channels for brain edema

Abstract

Cerebral edema is a pathological hallmark of various central nervous system (CNS) insults, including traumatic brain injury (TBI) and excitotoxic injury such as stroke. Due to the rigidity of the skull, edema-induced increase of intracranial fluid significantly complicates severe CNS injuries by raising intracranial pressure and compromising perfusion. Mortality due to cerebral edema is high. With mortality rates up to 80% in severe cases of stroke, it is the leading cause of death within the first week. Similarly, cerebral edema is devastating for patients of TBI, accounting for up to 50% mortality. Currently, the available treatments for cerebral edema include hypothermia, osmotherapy, and surgery. However, these treatments only address the symptoms and often elicit adverse side effects, potentially in part due to non-specificity. There is an urgent need to identify effective pharmacological treatments for cerebral edema. Currently, ion channels represent the third-largest target class for drug development, but their roles in cerebral edema remain ill-defined. The present review aims to provide an overview of the proposed roles of ion channels and transporters (including aquaporins, SUR1-TRPM4, chloride channels, glucose transporters, and proton-sensitive channels) in mediating cerebral edema in acute ischemic stroke and TBI. We also focus on the pharmacological inhibitors for each target and potential therapeutic strategies that may be further pursued for the treatment of cerebral edema.

Beneficial Effects on Brain Micro-Environment by Caloric Restriction in Alleviating Neurodegenerative Diseases and Brain Aging

“…Under stroke conditions, neuroinflammation can disrupt the BBB, whereby blood infiltrates the brain matter to induce vascular edema (Yang et al, 2019). Specifically, cerebrovascular edema caused by acute ischemic stroke and traumatic brain injury (TBI) further exacerbates BBB dysfunction by disrupting the balance between transporter and ion channels (Luo et al, 2020). In mouse models of transient middle cerebral artery occlusion, the AQP4 expression level in astrocytes was rapidly up-regulated following stroke and correlated with the degree of edema over time (Ribeiro Mde et al, 2006).…”

“…On the other hand, AQP4 knockout in mice revealed intact BBB structure, which resulted in significantly reduced mortality, infarction, and cerebral edema after stroke as well as improvement in long-term neurobehavioral performance (Manley et al, 2000;Yao et al, 2015). Moreover, the sulfonylurea receptor 1 (SUR1)-transient receptor potential melastatin 4 (TRPM4) pathway is closely associated with cerebral edema formation, and conversely, SUR1-TRPM4 inhibitors reduce brain swelling and improve clinical outcomes following acute ischemic stroke or TBI (Luo et al, 2020). In addition, recent research has demonstrated that SUR1-TRPM4 and AQP4 form a novel heterooligomer that amplifies ion/water osmotic coupling and drives astrocyte swelling (Stokum et al, 2018), which coordinate to affect brain edema.…”

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

“…TRPM4 is Ca 2+ activated, and is one of only two known ion channels in the mammalian genome that exclusively and non-selectively conducts monovalent cations [ 5 , 58 ]. TRPM4 is an independently functional ion channel, whereas SUR1 requires binding to a pore-forming subunit for functional capability [ 59 , 60 ].…”

TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons

“…Moreover, TRPM4 knockout mice show a variety of deficits in hippocampus-related behavioral tasks linked to decreased LTP ( Bovet-Carmona et al, 2018 , 2019 ). TRPM4 is also involved in neuronal degeneration and ischemia/reperfusion damage ( Schattling et al, 2012 ; Leiva-Salcedo et al, 2017 ), where it plays a key role in oncotic cell swelling and neuronal death, leading to the proposal that TRPM4 inhibition could be a treatment for these conditions ( Jha et al, 2020 ; Luo et al, 2020 ; Robert et al, 2020 ).…”