Inflammopharmacology · 2026
Neuroprotective effects of dapansutrile in rotenone-induced parkinsonism: targeting NLRP3/caspase-1, NF-κB, Nrf2/HO-1, and PINK1/Parkin pathways.
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Alqahtani Saad Misfer, Abdel-Wahab Basel A, El-Shoura Ehab A M, Kozman Magy R, Abdelzaher Lobna A, Mahmoud Nesreen I, Selim Hend Mostafa, Gad Mohamed A, Mohamed Sherif A, Rashwan Eman K, Saad Hebatallah M, Gaafar Ahmed, Gowifel Ayah M H
Аннотация
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.
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.