title: Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis.
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.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Arunava
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Suresh Babu
authors.initials: SB
authors.lastname: Rangasamy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Khushbu K
authors.initials: KK
authors.lastname: Modi
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Kalipada
authors.identifier: 0000-0001-6048-9598
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology* / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D008136:Longevity / Q000187:drug effects*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000473:pathology; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D000091346:Tripeptidyl-Peptidase 1; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494820:Bad protein, mouse; D000960:Hypolipidemic Agents; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D051025:bcl-Associated Death Protein; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D015248:Gemfibrozil
keywords: anti-inflammation; apoptosis; batten disease; gemfibrozil; longevity; mouse model