title: Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction.
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.
authors: Faculty of Pharmacy, Campus Puncak Alam, Universiti Teknologi MARA (UiTM), 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia, atishprakash@gmail.com.
authors: Atish
authors: A
authors: Prakash
authors: Anil
authors: A
authors: Kumar
authors: Long Chiau
authors: LC
authors: Ming
authors: Vasudevan
authors: V
authors: Mani
authors: Abu Bakar Abdul
authors: AB
authors: Majeed
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000633:toxicity; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015850:Interleukin-6; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013311:Streptozocin; D053148:Caspase 3; D019331:NG-Nitroarginine Methyl Ester; D000077205:Pioglitazone