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A2AR antagonists triggered the AMPK/m-TOR autophagic pathway to reverse the calcium-dependent cell damage in 6-OHDA induced model of PD.
Sophronea, Tuithung; Agrawal, Saurabh; Kumari, Namrata; Mishra, Jyoti; Walecha, Vaishali; Luthra, Pratibha Mehta.
Afiliación
  • Sophronea T; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India.
  • Agrawal S; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India.
  • Kumari N; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India.
  • Mishra J; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India.
  • Walecha V; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India.
  • Luthra PM; Neuropharmaceutical Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, North Campus, University of Delhi, Delhi, 110007, India. Electronic address: pmluthra@acbr.du.ac.in.
Neurochem Int ; 178: 105793, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38880232
ABSTRACT
Calcium dyshomeostasis, oxidative stress, autophagy and apoptosis are the pathogenesis of selective dopaminergic neuronal loss in Parkinson's disease (PD). Earlier, we reported that A2A R modulates IP3-dependent intracellular Ca2+ signalling via PKA. Moreover, A2A R antagonist has been reported to reduce oxidative stress and apoptosis in PD models, however intracellular Ca2+ ([Ca2+]i) dependent autophagy regulation in the 6-OHDA model of PD has not been explored. In the present study, we investigated the A2A R antagonists mediated neuroprotective effects in 6-OHDA-induced primary midbrain neuronal (PMN) cells and unilateral lesioned rat model of PD. 6-OHDA-induced oxidative stress (ROS and superoxide) and [Ca2+]i was measured using Fluo4AM, DCFDA and DHE dye respectively. Furthermore, autophagy was assessed by Western blot of p-m-TOR/mTOR, p-AMPK/AMPK, LC3I/II, Beclin and ß-actin. Apoptosis was measured by Annexin V-APC-PI detection and Western blot of Bcl2, Bax, caspase3 and ß-actin. Dopamine levels were measured by Dopamine ELISA kit and Western blot of tyrosine hydroxylase. Our results suggest that 6-OHDA-induced PMN cell death occurred due to the interruption of [Ca2+]i homeostasis, accompanied by activation of autophagy and apoptosis. A2A R antagonists prevented 6-OHDA-induced neuronal cell death by decreasing [Ca2+]i overload and oxidative stress. In addition, we found that A2A R antagonists upregulated mTOR phosphorylation and downregulated AMPK phosphorylation thereby reducing autophagy and apoptosis both in 6-OHDA induced PMN cells and 6-OHDA unilateral lesioned rat model. In conclusion, A2A R antagonists alleviated 6-OHDA toxicity by modulating [Ca2+]i signalling to inhibit autophagy mediated by the AMPK/mTOR pathway.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Calcio / Oxidopamina / Serina-Treonina Quinasas TOR Límite: Animals Idioma: En Revista: Neurochem Int Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Calcio / Oxidopamina / Serina-Treonina Quinasas TOR Límite: Animals Idioma: En Revista: Neurochem Int Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido