Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories

Abstract

Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R–mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity. Graphical abstract

The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis

“…In an animal study, cilostazol deactivated the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome [ 74 ], which is associated with atherosclerosis and CVD [ 75 , 76 ]. This anti-inflammatory potential was mediated by the downregulation of p65 NF-κB and the enhancement of sirtuin-1, leading to the downregulation of NLRP3, an apoptosis-associated speck-like protein, active caspase-1, and interleukin-1β [ 74 ].…”

“…In an animal study, cilostazol deactivated the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome [ 74 ], which is associated with atherosclerosis and CVD [ 75 , 76 ]. This anti-inflammatory potential was mediated by the downregulation of p65 NF-κB and the enhancement of sirtuin-1, leading to the downregulation of NLRP3, an apoptosis-associated speck-like protein, active caspase-1, and interleukin-1β [ 74 ]. In an animal study of hypercholesterolemic rats, cilostazol treatment protected against hypercholesterolemia-induced cardiac damage via molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-κB inhibition in the heart [ 77 ].…”

“…These effects depended mainly on the anti-inflammatory and antiapoptotic effects of cilostazol, which are mediated by scavenging hydroxyl radicals, decreasing the formation of tumor necrosis factor-α (TNF-α), and inhibiting adenosine diphosphate-ribose polymerase activity [ 138 ]. Moreover, cilostazol treatment improved neuronal survival by promoting the Akt and CREB, as well as brain-derived neurotrophic factor content in a rat model [ 74 ]. The production of NO triggered by cilostazol therapy via the activation of endothelial NO synthase also contributed to neuroprotection via endothelial protection [ 139 ].…”

The cell‐specific roles of Nrf2 in acute and chronic phases of ischemic stroke

“…Over the past several decades, multiple studies have reported the role of Nrf2 in the mitigation of neuronal excitotoxicity. 33 , 34 , 35 , 36 Nevertheless, excitotoxicity owing to acute neurovascular insult typically results in irreversible necrotic cell death within minutes, which is hardly preventable or rescuable. Although Nrf2 has been studied extensively, the mechanism(s) of its neuroprotective effects is not fully understood and requires further research.…”

“…Excitotoxicity is a common way of neuronal death not only seen in acute brain ischemia but also present in other diseases such as chronic ischemia, trauma, and neurodegenerative disorders. Over the past several decades, multiple studies have reported the role of Nrf2 in the mitigation of neuronal excitotoxicity 33–36 . Nevertheless, excitotoxicity owing to acute neurovascular insult typically results in irreversible necrotic cell death within minutes, which is hardly preventable or rescuable.…”