BBPT attenuated 6-OHDA-induced toxicity by modulating oxidative stress, apoptotic, and inflammatory proteins in primary neurons and rat models of Parkinson's disease

• Published in: Neurotoxicology (Park Forest South) 2024-12, Vol.105, p.67-81
• Main Authors: Mishra, Jyoti, Walecha, Vaishali, Sophronea, Tuithung, Singh, Ankit, Agrawal, Saurabh, Luthra, Pratibha Mehta
• Format: Article
• Language: English
• Subjects: 6-OHDA; A2A R antagonists; Animals; Apoptosis - drug effects; BBPT; Cells, Cultured; Disease Models, Animal; Dopamine - metabolism; Male; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Oxidopamine - toxicity; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Parkinson’s disease; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Thiazoles - pharmacology
• ISSN: 0161-813X; 1872-9711; 1872-9711
• DOI: 10.1016/j.neuro.2024.08.008

Parkinson’s disease (PD) results from the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Adenosine A2AR acting through the striato-pallidal pathway has emerged as a non-dopaminergic target in the therapy of PD. In the present work, the anti-parkinsonian potential of (4E)-4-(4-bromobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxo- thiazole-5-carbonitrile (BBPT) was explored. BBPT exhibited significant antioxidant activity in situ. In the MTT assay, the BBPT treatment showed insignificant toxicity to the primary midbrain neuronal (PMDN) cells. 6-OHDA induced PMDN cells, 3 h post-treated with BBPT showed 80–85 % survival of the cells and restoration of dopamine and TNF-α levels. The acute and sub-acute toxicity test for BBPT was performed with Sprague Dawley (SD) rats. In toxicity assay, any significant physical, hematological, or biochemical changes in the rats were not observed. To evaluate the effect of BBPT in vivo, a 6-OHDA-induced unilaterally lesioned SD rat model of PD was established. We observed that the BBPT treatment improved the behavioral symptoms in 6-OHDA-induced unilaterally lesioned rats. The proteins of 6-OHDA-induced BBPT-treated rats were isolated from the brain tissue to assess the antioxidant effect (GSH, catalase, SOD, lipid-peroxidation, nitrite), dopamine levels, and the restoration in the apoptosis and inflammation. Our results demonstrated that BBPT increased the anti-oxidant enzyme levels, restored the caspase-3/Bcl-2 levels to arrest apoptosis, and attenuated the TNF-α/IL-6 levels, thus restoring the neuronal damage in unilaterally lesioned 6-OHDA-induced SD rats. Precisely, the findings suggested that BBPT possessed significant anti-parkinsonian activity and has the potential to prevent dopaminergic neurodegeneration. [Display omitted] •BBPT restored dopamine and TNF- α levels in 6-OHDA-induced PMDN cells.•BBPT was found to be non-toxic in acute and sub-acute toxicity in rats.•BBPT reduced motor and non-motor deficits in the 6-OHDA-induced rats.•BBPT effectively attenuated oxidative stress in rat models of PD.