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Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by impaired memory function and oxidative damage. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through modulating nitric oxide synthase. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. The present study was designed to investigate the possible nitric oxide mechanism in the protective effect of pioglitazone against streptozotocin (STZ)-induced memory dysfunction. Wistar rats were intracerebroventricularly (ICV) injected with STZ. Then rats were treated with pioglitazone, NO modulators [l-arginine and nitro-l-arginine methyl ester (L-NAME)] for 21 days. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and mito-oxidative parameters, TNF-α, IL-6, and caspase-3 activity were measured. STZ-treated rats showed a memory deficit and significantly increased in mito-oxidative damage and inflammatory mediators and apoptosis in the hippocampus. Chronic treatment of pioglitazone significantly improved memory retention and attenuated mito-oxidative damage parameters, inflammatory markers, and apoptosis in STZ-treated rats. However, l-arginine pretreatment with lower dose of pioglitazone has not produced any protective effect as compared to per se. Furthermore, pretreatment of L-NAME significantly potentiated its protective effect, which indicates the involvement of nitric oxide for activation of PPAR-γ action. These results demonstrate that pioglitazone offers protection against STZ-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, and anti-apoptotic action mediating nitric oxide pathways and, therefore, could have a therapeutic potential in AD.

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Authors and Affiliations

  1. Faculty of Pharmacy, Campus Puncak Alam, Universiti Teknologi MARA (UiTM), 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia

    Atish Prakash, Long Chiau Ming, Vasudevan Mani & Abu Bakar Abdul Majeed

  2. Brain Degeneration and Therapeutics Group, Brain and Neuroscience Communities of Research, Universiti Teknologi MARA (UiTM), 40450, Shah Alam, Selangor Darul Ehsan, Malaysia

    Atish Prakash, Long Chiau Ming, Vasudevan Mani & Abu Bakar Abdul Majeed

  3. Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University, Chandigarh, 160014, India

    Atish Prakash & Anil Kumar

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  1. Atish Prakash
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  2. Anil Kumar
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Prakash, A., Kumar, A., Ming, L.C. et al. Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction. J Mol Neurosci 56, 739–750 (2015). https://doi.org/10.1007/s12031-015-0508-7

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