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 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, upregulated 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.

Effect of atorvastatin on Aβ1–42-induced alteration of SESN2, SIRT1, LC3II and TPP1 protein expressions in neuronal cell cultures

“…[39] Moreover, FDA-approved lipid-lowering, anti-inflammatory and effective drug in lysosomal biogenesis, gemfibrozil, prolonged life in CLN2 À/À mice, improved motor damage, decreased stored lysosomal material, decreased neuronal apoptosis and increased anti-inflammatory factors and thus to have neuronal protective properties. [40] In our study, although we found that Ab administration resulted in a significant decrease in TPP1 enzyme expression, atorvastatin does not have a significant effect on this decrease ( Figure 6), and therefore, atorvastatin/ HMG-CoA inhibition had no effect on lysosomal enzyme TPP1 expression. We suggested that atorvastatin effected on Ab 1-42 -induced autophagosome formation without effecting specific lysosomal enzyme TPP1.…”

“…[39] Moreover, FDA-approved lipid-lowering, anti-inflammatory and effective drug in lysosomal biogenesis, gemfibrozil, prolonged life in CLN2 À/À mice, decreased stored lysosomal material. [40] However, the effects of statins on neuroprotective SESN2 and SIRT1, and on the autophagy marker LC3II and the lysosomal enzyme TPP1 are unknown. Therefore, in the present study, we investigated the effect of atorvastatin on the SESN2, SIRT1, LC3II and TPP1 levels in the Ab 1-42stimulated human neuroblastoma cells (SH-SY5Y).…”

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

“…The FDAapproved lipidlowering drug gemfibrozil a lso a ctivates t he s ame p athway 81,82 a nd h as moderate beneficial effects in Cln2 mice. 83,84 A clinical trial to test efficacy of these approaches is yet to be launched in patients with any form of NCLs. Drug approaches for NCLs could com pensate for missing functional activities and slow or prevent cell death and these treatments will probably be used to supplement other treatments and methods such as gene therapy.…”

Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARα: Implications for late-infantile Batten disease therapy

“…The Cln2 targeted mutant mice (Cln2 −/− ) successfully recapitulates many of the LINCL characteristics including tremor, ataxia, neuronal pathology marked by lysosomal storage material, axonal degeneration and reduced lifespan (42). In a previous study, we demonstrated that Gemfibrozil, a FDA approved PPARα agonist, increased the lifespan of Cln2 −/− model of LINCL (43). Gemfibrozil-treated mice had reduced burden of storage granules, enhanced expression of anti-inflammatory and anti-apoptotic factors and lowered neuronal apoptosis compared to vehicle treated Cln2 −/− mice (43).…”

“…The following primers were used for PCR reactions to amplify fragments flanking the RXR-binding element on the mouse Cln2 promoter: Set1, sense 5′-CAG CTG CCA TGT CCC CCA GC-3′ and antisense 5′-TGC GCA GCT CTG TGT CAT CCG-3′; Set2, sense 5′-GCT CCC TCT CCT CAG CTG CCA-3′ and antisense 5′-CAT CCG GAG GCT CCA GGC CA-3′(34). The PCR reaction was standardized by using varying cycle numbers and different amounts of templates so that the results were in the linear range of PCR (34,35).…”