Abstract
Pyroptosis is a proinflammatory form of regulated cell death that plays an important role in ischemic stroke. Gualou Guizhi granule (GLGZG) is a classic prescription that has been shown to exert neuroprotective effects against cerebral ischemia reperfusion injury. In the present study, we examined the involvement of pyroptosis and its associated mechanism in protecting nerve function. Methods. Primary neurons were exposed to oxygen-glucose deprivation and reperfusion (OGD/R) conditions in the presence or absence of GLGZG. Cellular viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assay. The number of apoptoic cells was detected by NeuN and NSE protein expression. The expression levels of the pyroptosis markers, namely, NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukin-18 (IL-18), and IL-1β were determined by quantitative real-time PCR analysis, western blot, and ELISA analyses as appropriate. Moreover, the expression levels of the PI3K/Akt pathway key proteins were determined by quantitative real-time PCR analysis and western blot assays. To determine the PI3K/Akt pathway involvement in GLGZG-mediated neuroprotection, the PI3K inhibitor LY294002 (LY, 10 μM) was added. The expression levels of NeuN, Akt, and p-Akt were evaluated. Results. It was found that GLGZG could inhibit OGD/R-induced cell apoptosis, increase neuronal cell viability, decrease the production of IL-18 and IL-1β, and downregulate the expression levels of pyroptosis markers (NLRP3, ASC, and caspase-1). Furthermore, GLGZG could modulate the PI3K/Akt signaling pathway. Pharmacological inhibition of the PI3K pathway not only abrogated the effects of GLGZG on Akt but also neutralized its prosurvival and antipyroptotic actions. Conclusions. The findings indicated that GLGZG pretreatment effectively reduced OGD/R-induced injury by inhibiting cell pyroptosis and activating the PI3K/Akt pathway. These data provide important evidence for the therapeutic applications of this regimen in ischemic stroke.
Highlights
Stroke, notably ischemic stroke, is a life-threatening disease, which is considered the most common cause of disability and mortality in the world [1, 2]
Active caspase-1 causes the proteolytic cleavage of pro-IL-1β and pro-IL-18 into their active forms and induces pyroptosis, a proinflammatory form of regulated cell death
Pyroptosis releases proinflammatory cytokines and danger signals [9]. e targeting of pyroptosis has gained considerable attention and may be considered a new therapeutic strategy for inflammation caused by cerebral ischemia and reperfusion injury
Summary
Notably ischemic stroke, is a life-threatening disease, which is considered the most common cause of disability and mortality in the world [1, 2]. Stroke is mainly classified as ischemic or hemorrhagic with the former accounting for more than 80% of all cases [4]. Ischemic stroke causes cerebral blood flow decline, which may lead to deprivation of brain oxygen and glucose supply, and subsequent induction of apoptosis, necrosis, and metabolic dysfunction in neuronal cells [5]. Administration of neuroprotective drugs is frequently used. These treatments are limited by a narrow therapeutic time window and secondary side effects [6]. These treatments are limited by a narrow therapeutic time window and secondary side effects [6]. erefore, novel therapeutic agents, which can exert endogenous protection, but Evidence-Based Complementary and Alternative Medicine can enhance the resistance of nerve cells to ischemia and hypoxia, are needed
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