Activation of Wnt/Beta-Catenin Signaling Pathway as a Promising Therapeutic Candidate for Cerebral Ischemia/Reperfusion Injury

Abstract

Stroke is one of the leading causes of mortality, and survivors experience serious neurological and motor behavioral deficiencies. Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur because of ischemia/reperfusion injury. Wnt signaling is an evolutionarily conserved signaling pathway that has been manifested to play a key role in embryo development and function maintenance in adults. Overactivation of Wnt signaling has previously been investigated in cancer-based research studies. Recently, abnormal Wnt signaling activity has been observed in ischemic stroke, which is accompanied by massive blood–brain barrier (BBB) disruption, neuronal apoptosis, and neuroinflammation within the central nervous system (CNS). Significant therapeutic effects were observed after reactivating the adynamic signaling activity of canonical Wnt signaling in different cell types. To better understand the therapeutic potential of Wnt as a novel target for stroke, we reviewed the role of Wnt signaling in the pathogenesis of stroke in different cell types, including endothelial cells, neurons, oligodendrocytes, and microglia. A comprehensive understanding of Wnt signaling among different cells may help to evaluate its potential value for the development of novel therapeutic strategies based on Wnt activation that can ameliorate complications and improve functional rehabilitation after ischemic stroke.

Stabilization of nuclear β‐catenin by inhibiting KDM2A mediates cerebral ischemic tolerance

“…Recently, the activation of the Wnt/β‐catenin signaling pathway has been proposed as an important target for cerebral ischemic therapy 38 . In this process, nuclear β‐catenin, a transcriptional co‐activator, is believed to be a sign for the activation of canonical Wnt/β‐catenin pathway 23,39 .…”

Acetylation, methylation, and ubiquitination of proteins in experimental ischemic stroke in mice: a bioinformatics analysis

“…Модификация первого (N-концевое ацетилирование) описана в Uniprot. В литературе имеются данные о связи β-катенина с нарушениями целостности гемато-энцефалического барьера при ишемии/реперфузии у мышей, а также с такими патологиями как фиброз печени, рост опухолей и ишемический инсульт [7]. Несмотря на то, что значимые различия имеются только для относительных значений (что как бы должно свидетельствовать в пользу изменения уровня модифицированных белков), существуют данные о повышенном содержанием β-катенина в мозге после инсульта [8].…”

“…Для 7 белков (или 9, считая гомологи; литературная ссылка указывает, что какая-либо связь белка с ишемией мозга была обнаружена при литературном поиске) обнаружена статистическая тенденция (p<0,1). К ним относятся: (1) A2ASS6 (Titin); учитывая роль титина в процессе сокращения поперечнополосатых мышц это, скорее всего, ложноположительный результат, обусловленный его колоссальными размерами и наличием вариаций в генах реальных мышей; (2) G5E829 (Plasma membrane calciumtransporting ATPase) [10]; (3) O70318 (Band 4.1-like protein 2); (4) P08551 (Neurofilament light polypeptide) [11]; (5) O88935 (Synapsin-1) [12]; (6) Q8K0U4 (Heat shock 70 kDa protein 12A) [13]; (7)(8)(9) группа из 3 высокогомологичных белков P11798, P28652, Q6PHZ2 (Calcium/calmodulin-dependent protein kinase type II subunit alpha, beta, delta) [14] для пептида LK(+14.02)GALLTTMLATR. Следует отметить, что белки O88935, Q8K0U4 и P11798 фигурировали и в нашей предыдущей работе [1].…”

Therapeutic Potential and Mechanisms of Novel Simple O-Substituted Isoflavones against Cerebral Ischemia Reperfusion

“…Cerebral IR injury is a vicious cycle, and its pathophysiological mechanisms include the failure of brain energy metabolism, disruption of ion homeostasis, excitotoxicity, calcium overload, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and inflammation. Then, apoptotic- and autophagy-related enzymes and genes are activated to cause neuronal necrosis and apoptosis, subsequently decreasing intracellular signaling transduction and cerebral nerve functions, such as motor and neurobehavior function [ 8 , 9 , 13 , 14 , 15 , 17 , 22 , 23 ]. Due to the causes and pathophysiological cascades of IR, oxygen deprivation (hypoxia), oxygen and glucose deprivation (OGD), and treatment with excitotoxic toxins (such as glutamate or N-methyl-D-aspartate (NMDA)) are commonly used in in vitro research models.…”