Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis.
Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motoneuron death in amyotrophic lateral sclerosis (ALS) both in humans and transgenic mouse models. Peroxisome proliferator-activated receptors (PPARs) are involved in the inflammatory process. Agonists of PPAR-alpha, -gamma, and -delta show anti-inflammatory effects both in vitro and in vivo. We investigated the therapeutic effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, in the G93A SOD1 transgenic mouse model of ALS. Orally administered pioglitazone improved motor performance, delayed weight loss, attenuated motor neuron loss, and extended survival of G93A mice as compared to the untreated control littermate group. Pioglitazone treatment extended survival by 13%, and it reduced gliosis as assessed by immunohistochemical staining for CD-40 and GFAP. Pioglitazone also reduced iNOS, NFkappa-B, and 3-nitrotyrosine immunoreactivity in the spinal cords of G93A transgenic mice. These results suggest that pioglitazone may have therapeutic potential for human ALS.
Kiaei
Mahmoud
M
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, 525 East 68th Street, Room A-501, New York, NY 10021, USA. mak2026@med.cornell.edu
Kipiani
Khatuna
K
Chen
Junyu
J
Calingasan
Noel Y
NY
Beal
M Flint
MF
D000284:Administration, Oral; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D005911:Gliosis / Q000473:pathology; D008161:Lumbosacral Region; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011597:Psychomotor Performance / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D015996:Survival Rate; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D016328:NF-kappa B; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000077205:Pioglitazone