Cilostazol or canagliflozin mitigates Cyclosporine A-induced nephrotoxicity by modulating the STAMP2-mTOR-AMPK signaling pathway and autophagy in a rat model.

Cilostazol-loaded acellular vascular graft for suppressing intimal hyperplasia.

Introduction: The prevalence of executive dysfunctions and attention deficits is increasingly recognized among patients with atherosclerotic cardiovascular disease (ASCVD). Cilostazol (CLZ) and pentoxifylline (PTX) are two potential therapeutic agents that may help reduce the risk of cognitive decline in these patients, likely due to their anti-inflammatory, vasodilatory and endothelial protective effects. However, their comparative efficacy remains unknown. Research Question: CLZ or PTX, which drug is effective in reducing cognitive dysfunctions in ASCVD patients? Methods: A systematic review (SR) was conducted following a comprehensive literature search including RCTs, narrative review, retrospective, and prospective studies. The individual effects of both therapies were evaluated with respect to their potential to reduce vascular stress and improve cognitive dysfunction. Results: This SR compares CLZ versus PTX in 19,966 subjects across 6 studies carried out in 4 countries including Brazil, Japan, Taiwan, and the United States. PTX significantly reduced C-reactive protein (CRP) (P=0.04), Tumor Necrosis Factor-alpha (TNF-α) (P<0.01) levels, and attenuated the decline in Interleukin-10 (IL-10) compared to placebo (P<0.01), thereby suggesting a potential anti-inflammatory effect (Fernandes et al). Additionally, it enhances blood flow by promoting fibrinolysis, improving erythrocyte flexibility, and reducing neutrophil activation (McCarty et al). On the contrary, CLZ was associated with a 25% reduction in dementia risk (HR 0.75; 95%CI, 0.61–0.92) (Tai et al), and significantly reduced the risk of ischemic (OR 0.68; 95%CI, 0.57–0.81; P<0.0001) and hemorrhagic (OR 0.43; 95%CI, 0.29–0.64; P=0.0001) stroke with a lower risk of bleeding (McHutchison et al). However, RCTs showed no significant improvement in Mini-Mental State Examination (MMSE) scores with cilostazol over 96 weeks (Saito et al). Additionally, post-stroke cognition did not improve significantly, with elevated M1 macrophages potentially contributing to neurological decline (Huang et al). While both drugs show promising effects, CLZ has more supportive cognitive data. Conclusion: Based on current evidence, CLZ and PTX show potential in mitigating cognitive dysfunctions in ASCVD. CLZ has more data linking to reduced dementia and stroke risk, while PTX shows strong anti-inflammatory benefits. If confirmed by future trials, both therapies could be integrated into guidelines as adjuncts for selected patients.

Cilostazol and SB203580 combination: Targeting ER stress and p38MAPK signaling in Alzheimer's disease mouse model.

We conducted a prospective, randomized study to evaluate the combination of cilostazol (CTZ) and extract of Ginkgo biloba (EGb) and compare it with aspirin for the prevention of atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM). One hundred five patients with T2DM and increased carotid intima-media thickness (IMT) were randomly assigned to receive either CTZ 200 mg plus EGb 160 mg once daily or aspirin (ASA) 100 mg/day for 12 months. The primary endpoint was the change in maximum carotid IMT. The mean age and body mass index were 61.6±8.4 years and 25.2±3.1 kg/m2 in the CTZ/EGb group and 61.6±7.6 years and 24.5±3.3 kg/m2 in the ASA group, respectively. CTZ/EGb treatment reduced the maximum IMT in the bulb area (from 1.435±0.690 to 1.346±0.688 mm on the right; from 1.359±0.528 to 1.299±0.528 mm on the left), whereas ASA treatment did not, resulting in significant between-group differences (P<0.05). No significant differences were observed in the common carotid and internal carotid arteries. The CTZ/EGb group showed a reduction in triglycerides and an increase in high-density lipoprotein cholesterol levels. Additionally, aspartate and alanine aminotransferase levels decreased only in the CTZ/EGb group. There were no significant differences in Mini-Mental State Examination (MMSE) score changes or adverse events (ClinicalTrials.gov number: NCT05906199). Twelve months of CTZ/EGb combination therapy significantly attenuated the progression of carotid atherosclerosis compared with aspirin in patients with T2DM.

Deep vein thrombosis (DVT) is the third major leading cause of mortality and morbidity after cardiovascular disease and stroke. Cilostazol (CLZ) being one of the antiplatelet agents is effectively used in DVT. However, its oral administration is associated with several problems, such as gastrointestinal side effects and extensive first-pass metabolism. Herein, CLZ-loaded transethosomes (CLZ-TEs) were prepared and incorporated in chitosan gel (CLZ-TEG) for transdermal administration. Box-Behnken Design Expert® software was used to statistically optimize CLZ-TEs. Particle properties, Transmission electron microscopy (TEM), and Fourier Transform Infrared spectroscopy (FTIR) analyses of CLZ-TEs were accomplished followed by in vitro release and permeation studies and its comparison with CLZ-TEG, CLZ-dispersion (Ds) and CLZ-G. Moreover, skin irritation and pharmacokinetics studies of the optimized CLZ-TEG were executed. The optimized CLZ-TEs showed a mean particle size of 174 nm, polydispersity index of 0.173, zeta potential of −30 mV, and entrapment efficiency of 99%. TEM exhibited spherical nanovesicles and FTIR demonstrated compatibility of the excipients. Moreover, CLZ-TEG was homogeneous, smooth, and spreadable. Similarly, CLZ-TEG displayed sustained release and enhanced permeation of the CLZ. Furthermore, pharmacokinetic study showed significantly improved (p < 0.05) bioavailability of CLZ-TEG when compared with CLZ-G and CLZ-Ds. It was concluded that CLZ-TEG may be a potential candidate for the management of DVT.

Cilostazol attenuates cisplatin-induced acute liver injury by targeting the SIRT1/AMPK/PGC-1α signaling pathway, with an impact on miRNA-34a.

Cilostazol (CTZ), is a BCS class II drug with limited bioavailability. In the current study, orally disintegrating tablets (ODTs) for buccal delivery of CTZ were prepared by two methods; lyophilization (Lyo-ODTs) and direct compression (DC-ODTs). All CTZ-ODTs were evaluated for in vitro disintegration time (DT) and wetting time (WT) tests, in vitro dissolution. Scanning electron microscopic (SEM) analysis was performed for the selected Lyo-ODT-7 and DC-ODT-2. Lyo-ODT-7 composed of aerosil® 200 and PEG 4000 acquired the shortest DT (13.00 ± 0.14) and WT (33.00 ± 0.26) among the prepared ODTs. It also showed a 2.3 fold significantly enhanced dissolution profile at an early time point (5 min) that was maintained till 1 h, in simulated saliva fluid (pH ∼ 6.8), compared to Pletaal® IR tablets (p < 0.0001). SEM analysis revealed the remarkable porosity of Lyo-ODT-7, confirming its successfully enhanced disintegration and dissolution. Lyo-ODT-7 showed significantly enhanced pharmacokinetic parameters with a 3.5 and 3.6 fold increase in Cmax (p = 0.0493) and AUC0-24 (p = 0.0470), respectively compared to Pletaal® IR tablets. The relative bioavailability of CTZ after buccal administration of Lyo-ODT-7 to rats was 364.45%, compared to the market oral IR tablets; Pletaal®. The enhanced bioavailability imposes the successful oromucosal absorption of CTZ via buccal delivery of Lyo-ODT-7. Our study demonstrated that Lyo-ODT-7 could represent a favorable buccal dosage form for patients with intermittent claudication, suffering from dysphagia. It can also be used in cases of acute cerebral or myocardial infarction due to its significantly enhanced rate and extent of absorption. It is considered a promising approach for buccal delivery of BCS class II active pharmaceutical ingredients (APIs) suffering from solubility problems and hepatic first pass effect.

Cilostazol (CIL), a BCS class II antiplatelet aggregation and vasodilator agent, is used for cerebrovascular diseases to minimize blood-brain barrier dysfunction, white matter-lesion formation, and motor deficits. The current work aimed to develop and optimize cilostazol-loaded spanlastics (CIL-SPA) for nose-to-brain delivery to overcome the low solubility and absorption, the first pass-metabolism, and the adverse effects. The optimal CIL-SPA formulation was loaded into Phytagel® (SPA-PG), Poloxamer-407 (SPA-P407), and chitosan (SPA-CS) gel bases and characterized in terms of colloidal properties, encapsulation efficiency (EE%), mucoadhesive properties, and biopharmaceutical aspects. The developed in situ gelling formulations showed a <300 nm average hydrodynamic diameter, <0.5 polydispersity index, and >|±30| mV zeta potential with a high EE% (>99%). All formulations met the droplet size-distribution criteria of nasal requirements (<200 µm), and all formulations showed adequate mucoadhesion properties. Both the BBB-PAMPA and horizontal permeability study through an artificial membrane revealed that all formulations had higher CIL flux and cumulative permeability at in vitro nose-to-brain conditions compared to the initial CIL. The in vitro drug-release study showed that all formulations released ca. 100% of CIL after 2 h. Therefore, the developed formulations could be promising for improving the low bioavailability of CIL through nose-to-brain delivery.

To investigate the clinical effect of anti-platelet aggregation drugs combined with Shujin Huoluo Decoction (SJHLD, a decoction for relaxing muscles and activating collaterals) in the treatment of diabetic peripheral vascular disease. A total of 130 patients with diabetic peripheral vascular disease were retrospectively included in this study and divided into two groups. In the monotherapy group, 65 patients were treated with cilostazol (CTZ) monotherapy; in the combined group, 65 patients were treated with CTZ combined with SJHLD. The treatment efficacy, inflammatory indexes, blood glucose and lipid levels, ultrasound parameters, and hemorheology of the two groups were compared before and after treatment. Both groups showed significant improvements in walking distance and skin temperature of the toes, with more pronounced changes observed in the combined group (P < 0.05). After treatment, inflammatory markers decreased notably in both groups (P < 0.05). Blood glucose and lipid levels decreased markedly, with a more substantial reduction in lipid levels observed in the combined group (P < 0.05). Lower limb arterial conditions improved markedly in both groups, with greater improvements seen in the combined group (P < 0.05). Additionally, the pulsatile index and blood flow velocity in the ankle-brachial and dorsalis pedis arteries increased markedly in both groups, with the combined group showing a greater improvement (P < 0.05). Hemorheology parameters also decreased significantly in both groups, with the combined group showing a more significant reduction (P < 0.05). The effective treatment rate was significantly higher in the combined group (P < 0.05). The combination of CTZ and SJHLD significantly improves lower limb function, ultrasound parameters, and blood flow, enhancing treatment efficiency in patients with diabetic peripheral vascular disease. This therapeutic approach offers valuable clinical guidance and warrants consideration for use in diabetic patients.

Currently, there is a lack of targeted medications for estrogen-induced intrahepatic cholestasis (EIC) and the primary objective in managing this condition is to safeguard liver function. Consequently, this study was conducted to examine the pharmacological efficacy of cilostazol (CTZ) in the management of EIC and explore its underlying mechanisms through the use of an animal model. Thirty female Sprague-Dawley rats were divided into five groups of six animals each: Normal group, 17-ethinylestradiol (EE)-induced intrahepatic cholestasis group, EE + ursodeoxycholic acid (UDCA)-treated group, EE + CTZ (5 mg/kg)-treated group, and EE + CTZ (10 mg/kg)-treated group. It was found that the therapeutic efficacy of UDCA and low dosage of CTZ (5 mg/kg) was comparable. Nevertheless, when CTZ was administered at a dose of 10 mg/kg, it resulted in the normalization of all liver function parameters, oxidative stress, and pro-inflammatory markers, together with improvement in the histopathological derangements and hepatocytic apoptosis. These effects were mediated through the activation of the hepatocyte nuclear factor-1 alpha (HNF1α)/Farnesoid X receptor (FXR) pathway with subsequent down-regulation of the bile acids (BAs) synthesis enzyme; cholesterol 7α-hydroxylase (CYP7A1), and up-regulation of the BAs-metabolizing enzyme; cytochrome P450 (CYP)3A1 and the bile salt export pump; BSEP. Therefore, the administration of CTZ in a dose-dependent manner can protect against EIC through regulating the HNF1α/FXR pathway and anti-apoptotic mechanisms. This implies that CTZ exhibits considerable promise as a therapeutic agent for the treatment of cholestatic liver disorders.

Background Mirabegron (MIRG) is a type of β3 adrenoceptor agonist that is considered an alternative therapy for the treatment of overactive bladder (OAB) symptoms. Cilostazol (CITZ) is a selective inhibitor of phosphodiesterase (III) that has various pharmacological effects. Objectve The current study aimed to highlight the regulatory effects of CITZ on MIRG-induced toxicity. Materials and Methods Male rats were divided into six groups. Blood samples were collected to determine different hepatic and kidney function levels along with serum protein electrophoresis and inflammatory factor levels. Histopathological studies and oxidative stress (OS) were also assessed. Kidney and hepatic damage were detected following the administration of MIRG, especially at high doses, due to elevated OS, inflammation, and apoptotic marker levels. Results Rats receiving CITZ exhibited significant improvements in both hepatic and kidney functions, with decreased inflammation and OS. Conclusion CITZ administration plays a beneficial role in alleviating hepatic and nephrotoxicity induced by MIRG by inhibiting OS and inflammation.

This study aims to elucidate the effect of alprostadil (ALP) plus cilostazol (CIL) on the treatment outcomes and inflammatory factors in patients with lower extremity arteriosclerosis obliterans (LEASO) receiving evidence-based care. Firstly, 130 patients with LEASO were selected from February 2020 to February 2023 and then randomly divided into two groups with 65 patients each. Excluding the dropouts, 59 patients in the control group (6 cases of dropout) received ALP and 62 patients in the research group (3 cases of dropout) received ALP plus CIL. Both groups were cared for in accordance with the evidence-based care model. Treatment outcomes, arteriosclerosis indexes (blood flow of dorsalis pedis artery [DPA], ankle-brachial index [ABI] and toe-brachial index [TBI]), hemorheological parameters (erythrocyte aggregation index [EAI], erythrocyte deformation index [EDI], high blood viscosity [HBV] and haematocrit [HCT]), inflammatory factors (interleukin [IL]-6, IL-8 and tumour necrosis factor [TNF]-α) and complications (nausea, diarrhoea, headache and transaminase elevation) were compared between the control and research groups. Results show that the overall response rate was markedly higher in the research group (90.32%) than in the control group (74.58%). Additionally, the blood flow of DPA, ABI and TBI in the research group significantly increased after the treatment and were higher than those in the control group. Meanwhile, the EAI, EDI, HBV, HCT, IL-6, IL-8 and TNF-α were significantly lower. The two groups did not differ markedly in the complication rate. The above findings suggest that ALP plus CIL is effective for patients with LEASO receiving evidence-based care. It can significantly improve arteriosclerosis indexes and hemorheological parameters while inhibiting serum inflammatory responses, with some certain safety.

Novel insights into gut health: Cilostazol strengthens gut integrity by adjusting TLR-2/NF-κB/IL-23 and CD44/AKT/GSK-3β/cyclin-D1 trajectories in methotrexate-induced mucositis model

Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS+CZ (MCT+CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48h after MCT administration. Postoperative survival rates were evaluated (n=9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. The cumulative 10-day postoperative survival rate was significantly higher in the SOS+CZ group than in the SOS group (88.9% vs 33.3%, P=0.001). Total SOS scores were significantly lower in the SOS+CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS+CZ group than in the SOS group on POD 1 (86.1±8.2% vs 63.8±9.3%, P=0.003). Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Background: Intracerebral hemorrhage (ICH) is the deadliest form of stroke with no effective treatment to date. Toxic byproducts from hematoma-lysis affected ICH-induced brain injury and long-term behavioral impairment. Enhancing hematoma clearance has shown therapeutic potential in reducing brain damage and neurologic deficits. Our previous work shows that cilostazol (CSZ) promotes meningeal lymphangiogenesis and drainage, aiding hematoma resolution and brain recovery after ICH. Here we explore the optimal dosage, therapeutic window, and potential adverse effects of CSZ treatment in preclinical ICH. Methods: A dose of 200 mg/day CSZ is used in clinics which translates to around 40 mg/kg in mice. CSZ (10, 20, and 40 mg/kg) or vehicle was given after ICH induction and was continued for various durations. Pretreatment of CSZ before ICH induction was used to assess its antiplatelet property on intra-parenchymal bleeding. Meningeal lymphatic vessel (mLV) complexity and coverage rate were measured. Lymphatic drainage was evaluated by fluorescent microbead accumulation in the mLV and deep cervical lymph nodes. Neurobehaviors were tested by corner turn test, whisker-evoked tactile responses, hindlimb abduction test, and neurologic deficit scoring. Iron deposition, hematoma, and neuron loss were assessed by immunohistochemistry. Results: ICH mice treated with CSZ showed enhanced mLV complexity and proliferation at the transverse, superior sagittal, and confluence of sinuses in the meninges. In parallel, histological, and behavioral outcomes also improved. Pretreatment with CSZ for 3 days before ICH induction did not increase hematoma volume, suggesting minimal to no adverse anticoagulant effect of CSZ in this setting. Conclusion: In all, our results unfold the effects of CSZ on mLV function regarding ICH. These findings may be applied as outcome parameters and provide a roadmap for sample size estimation in future clinical trials using CSZ as ICH treatment.

Diabetes doubles the risk of VCID. The underlying reasons are not understood, and preventive therapeutic strategies are lacking. We showed that diabetic but not control rats develop a progressive cognitive decline in a microemboli (ME) model of VCID. Given that cerebrovascular dysfunction is a common pathology between diabetes and VCID, we hypothesized that improvement of endothelial function in diabetes prevents ME-mediated cognitive impairment. Our treatment paradigm was based on the recently reported LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (CZL) in the prevention of small vessel disease (SVD) progression. At 7-8 weeks after diabetes onset, control and diabetic rats were treated with ISMN/CZL for 4 weeks, then injected with cholesterol crystal ME and behavioral outcomes were monitored longitudinally for 16 weeks. Plasma biomarkers recommended by MarkVCID and D eterminants of I ncident S troke C ognitive O utcomes and V ascular E ffects on R ecover Y (DISCOVERY) Consortiums were measured using the angiogenesis (Flt-1, VEGF and FGF), neurology (GFAP, phosphoTau and Neurofilament Light NfL) and amyloid beta 42/40 panels from the Meso Scale Discovery. Behavioral deficits observed in the untreated diabetic rats were not noted in the treated group. Some of the biomarkers were unchanged (Table). This suggests that drug treatment with ISMN/CZL before ME injection prevented the possible deleterious effects of the latter in the diabetic rats by improving the endothelial integrity and it is a viable preventive and possibly therapeutic strategy for VCID.

Background: Diabetes is a prevailing disease worldwide and its complications are also hazardous including nephropathy. Drug available to treat Diabetic Nephropathy (DN) faces bioavailability issues related to solubility and absorption of drugs. Cilostazol (CLT) is a BCS class II drug that is poorly water-soluble which affects its therapeutic efficacy. CLT reduces reactive oxy-gen species (ROS) increased in DN. Curcumin (Cur) is also hydrophobic but Cur has many therapeutic efficacies like anti-inflammatory and antioxidant properties that help for the treatment of DN. Objective: The objective of the current study was to develop and optimize the Cilostazol Solid Dis-persion Nanoparticle (SDN) to improve the bioavailability of the drug by tagging it with Cur by us-ing PVP VA S 630 as polymer and Poloxamer 407 as surfactant. Method: Different formulations were developed using the emulsion solvent evaporation method, PVP VA S 630 as the hydrophilic polymer, and Poloxamer 407 as a surfactant. Two-factor, three-level Box-Behnken Design (BBD) was used for statistical analysis of the selected process variable's main effect and interactive effect on the response. Curcumin tagging was also done for the entire batches. Nanoparticles were characterized by FT-IR spectroscopy, DSC, Particle size, Zeta poten-tial, Drug entrapment efficiency, Solubility, and % CDR studies. Results: Among the 17 different formulations (CLT1-CLT 17), with a solubility of 39.5 μg/ml, a % CDR of 99.55, a typical particle size of 219.67 nm with a PDI of 0.258, entrapment efficiency of 73.47%, and a -10.6 mV of Zeta potential, CLT-15 was optimized. To determine CLT and curcu-min, the simultaneous UV calibration method was created. Overall, the DSC study indicated the amorphous nature of the Nano Dispersion, which in turn means the successful entrapment of the CLT in the Nano Dispersion matrix. TEM images also confirmed the spherical nanoparticles. The optimized batch of drugs tagged with curcumin was compared with the plain drug Solid Dispersion Nanoparticles. Conclusion: Together with the molecules of curcumin, the solid nano dispersion of CLT was pro-duced, which will add to the benefits of the management of Diabetic Nephropathy. In the current study, we underline the importance of utilising both API and phytochemicals in the treatment of Di-abetic Nephropathy, and we anticipate further basic research or clinical trials to support innovative treatments. It is possible to use these matrix-forming polymers for active ingredients with poor sol-ubility, whether they are natural or synthetic. It has also been demonstrated that these carriers (PVP VA S 630 &amp; Poloxamer) increase the dissolution rate (in-vitro).

Poly(amide-triazole) and poly(ester-triazole) synthesizedfrom d-galactose as a renewable resource were applied forthe synthesisof nanoparticles (NPs) by the emulsification/solvent evaporation method.The NPs were characterized as stable, spherical particles, and noneof their components, including the stabilizer poly(vinyl alcohol),were cytotoxic for normal rat kidney cells. These NPs proved to beuseful for the efficient encapsulation of cilostazol (CLZ), an antiplateletand vasodilator drug currently used for the treatment of intermittentclaudication, which is associated with undesired side-effects. Inthis context, the nanoencapsulation of CLZ was expected to improveits therapeutic administration. The carbohydrate-derived polymericNPs were designed taking into account that the triazole rings of thepolymer backbone could have attractive interactions with the tetrazolering of CLZ. The activity of the nanoencapsulated CLZ was measuredusing a matrix metalloproteinase model in a lipopolysaccharide-inducedinflammation system. Interestingly, the encapsulated drug exhibitedenhanced anti-inflammatory activity in comparison with the free drug.The results are very promising since the stable, noncytotoxic NP systemsefficiently reduced the inflammation response at low CLZ doses. Insummary, the NPs were obtained through an innovative methodology thatcombines a carbohydrate-derived synthetic polymer, designed to interactwith the drug, ease of preparation, adequate biological performance,and environmentally friendly production.

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