Neuroprotective effects of dapansutrile in rotenone-induced parkinsonism: targeting NLRP3/caspase-1, NF-κB, Nrf2/HO-1, and PINK1/Parkin pathways.
Neuroprotective effects of dapansutrile in rotenone-induced parkinsonism: targeting NLRP3/caspase-1, NF-κB, Nrf2/HO-1, and PINK1/Parkin pathways.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Najrān, SA · Author affiliation
Department of Pathology, College of Medicine, The University Hospital, Najran University, Najran, Saudi Arabia.Location evidence
Assiut, EG · Author affiliation
Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt. ehabel-shoura@azhar.edu.eg.Location evidence
Giza, EG · Author affiliation
Clinical Pharmacy Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, 12563, Egypt.Location evidence
Buraydah, SA · Author affiliation
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia.Location evidence
Tanta, EG · Author affiliation
Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.Location evidence
Damietta, EG · Author affiliation
Medical Biochemistry Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt.Location evidence
Zarqa, JO · Author affiliation
Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, 13110, Jordan.Location evidence
EG · Author affiliation · country only
Biochemistry Department, Faculty of Medicine, Al-Azhar University, Assuit, Egypt.Location evidence
SA · Author affiliation · country only
Department of Physiology, College of Medicine, Jouf University, Sakaka, Kingdom of Saudi Arabia.Location evidence
Port Said, EG · Author affiliation
Department of Pharmacology and Toxicology, Faculty of Pharmacy, East Port Said National University, Port Said, Egypt.Location evidence
Cairo, EG · Author affiliation
Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 11571, Egypt.Location evidence
A plain-language reading has not been prepared for this paper yet.
Original abstract
BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic dysfunction, neuroinflammation, oxidative stress, and mitochondrial abnormalities. Activation of the NLRP3 inflammasome has been implicated in PD pathophysiology; however, its relationship with other pathological processes remains incompletely understood. The present study investigated the neuroprotective effects of dapansutrile (DPST), a selective NLRP3 inhibitor, in a rotenone (ROTN)-induced rat model of parkinsonism and examined its effects on inflammation-, oxidative stress-, mitophagy-, and apoptosis-related markers. METHODS: Forty-four adult male Wistar rats were randomly allocated into four groups: control, DPST-treated control (200 mg/kg/day, p.o.), ROTN-treated (1.5 mg/kg, s.c., every other day for 21 days), and ROTN + DPST-treated groups. Behavioral assessments were conducted followed by biochemical, molecular, histopathological, and immunohistochemical analyses of brain tissues. Markers related to oxidative stress, inflammatory signaling, mitophagy-associated pathways, and apoptosis-associated signaling were evaluated. RESULTS: ROTN administration induced marked behavioral deficits, dopamine depletion, oxidative stress, neuroinflammation, histopathological alterations, and increased GFAP immunoreactivity. These changes were accompanied by increased NLRP3 expression, caspase-1 activity, IL-18 levels, and Apaf-1 expression, together with reduced PINK1, Parkin, and MFN1 protein expression. DPST treatment significantly improved behavioral performance, restored dopamine and BDNF levels, attenuated oxidative stress and inflammatory responses, reduced NLRP3-associated inflammatory markers, improved the expression of PINK1-, Parkin-, and MFN1-related proteins, and lowered Apaf-1 expression. Furthermore, DPST ameliorated the histopathological alterations and astroglial activation induced by ROTN. CONCLUSION: DPST exerted significant neuroprotective effects in the rotenone-induced rat model of parkinsonism. These beneficial effects were associated with modulation of NLRP3-associated inflammatory signaling, attenuation of oxidative stress, and alterations in mitophagy-related and apoptosis-related markers. While the findings support a potential role for NLRP3 signaling in ROTN-induced neurotoxicity, the present data establish associations rather than direct causal mechanisms. Further studies employing dedicated assessments of pyroptosis, mitophagic flux, mitochondrial function, apoptosis, and dopaminergic neuronal survival are required to clarify the mechanistic basis of DPST-mediated neuroprotection.