Gemfibrozil, food and drug administration‐approved lipid‐lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis. Issue 3 (3rd April 2017)

• Record Type: Journal Article
• Authors: Ghosh, Arunava; Rangasamy, Suresh Babu; Modi, Khushbu K.; Pahan, Kalipada
• Is Part Of: Journal of neurochemistry. Volume 141:Issue 3(2017)
• Page Start: 423
• Page End: 435
• Publication Date: 2017-04-03
• Subjects: anti‐inflammation -- apoptosis -- batten disease -- gemfibrozil -- longevity -- mouse model; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13987
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid‐protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL. Therefore, we administered gemfibrozil (gem), an food and drug administration (FDA)‐approved lipid‐lowering drug, which has been shown to stimulate lysosomal biogenesis and induce anti‐inflammation, orally, at a dose of 7.5 mg/kg body wt/day to Cln2 (−/−) mice. We observed that gem‐fed Cln2 (−/−) mice lived longer by more than 10 weeks and had better motor activity compared to vehicle (0.1% Methyl cellulose) treatment. Gem treatment lowered the burden of storage materials, increased anti‐inflammatory factors like SOCS3 and IL‐1Ra, up‐regulated anti‐apoptotic molecule like phospho‐Bad, and reduced neuronal apoptosis in the brain of Cln2 (−/−) mice. Collectively, this study reinforces a neuroprotective role of gem that may be of therapeutic interest in improving the quality of life in LINCL patients. Abstract : We have demonstrated that oral administration of gemfibrozil up‐regulates the expression of anti‐inflammatory molecules like interleukin‐1 receptor antagonist (IL‐1Ra) and suppressor of cytokine signaling 3 (SOCS3) in vivo in the brain of Cln2 null mice, an animal model of late infantile neuronal ceroid lipofuscinosis, leading to the suppression of neuronal apoptosis, increased survival, and improved locomotor activity.