Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is one of the most common adult onset neurodegenerative diseases. A major advance in understanding its pathogenesis came from the genetics that identified mutations in the gene coding for copper–zinc superoxide dismutase 1 (SOD1) in a subset of patients with autosomal dominant inherited ALS (Rosen et al., 1993). This led to the development of transgenic mouse models and spurred investigations into disease pathogenesis (Gurney, 1994, Wong et al., 1995). It has subsequently been demonstrated that activated microglia occur in transgenic mouse models of ALS (Hall et al., 1998). These are closely associated with disease pathogenesis.
The peroxisome proliferator-activated receptors (PPARs) are member of the nuclear receptor super family. PPARs are ligand dependent transcription factors that bind to specific peroxisome proliferator response elements and enhance the expression of regulated genes (Kielian and Drew, 2003). PPARs have been implicated in insulin sensitivity, adipocyte differentiation, and inflammatory processes. Numerous studies show that agonists of PPAR-α, -γ, and -δ exert anti-inflammatory effects both in vitro and in vivo (Youssef and Badr, 2004). PPARs down-regulate proinflammatory cytokines and iNOS in both macrophages and microglial cells (Colville-Nash et al., 1998, Jiang et al., 1998, Petrova et al., 1999, Ricote, 1998). Previous studies showed that PPAR-γ agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death in vitro and in vivo (Heneka et al., 1999, Heneka et al., 2000). They also protect against glutamate-mediated cell death in mixed cortical neuron and glia cocultures. Others reported that pioglitazone protected tyrosine hydroxylase (TH)-positive substantia nigra neurons from death induced by MPTP (Breidert et al., 2002, Dehmer et al., 2004). Pioglitazone treatment reduced activation of microglia, reduced induction of iNOS-positive cells and less glial fibrillary acidic protein-positive cells in both striatum and substantia nigra pars compacta of MPTP-treated mice (Dehmer et al., 2004). We therefore examined whether an agonist of PPAR-γ, an anti-inflammatory protein, could delay or slow the disease process in the G93A SOD1 transgenic mouse model of ALS.
Section snippets
Mice
G93A transgenic familial ALS mice (high expresser line) (Gurney, 1994) were obtained from The Jackson Laboratory (Bar Harbor, ME, U.S.A). We maintained the G93A transgenic homozygous mice by mating transgenic males with B6SJLF1/J hybrid females. Transgenic offspring were genotyped by PCR assay of DNA obtained from tail tissue.
Thirty-nine G93A SOD1 transgenic mice were randomly assigned to control (vehicle) and pioglitazone groups. Pioglitazone (Actos) was given in food at 1200 ppm to G93A SOD1
Pioglitazone treatment: motor performance and weight loss
Pioglitazone-treated mice had significantly better motor performance from 90 to 124 days of age compared to G93A mice fed the control diet (Fig. 1). Pioglitazone treatment resulted in a significant improvement in the weight loss of G93A mice from 95 days of age as compared with G93A mice treated with the control diet (data not shown). Control diet-treated G93A mice began losing weight from 95 days of age and rapidly declined, whereas pioglitazone-treated G93A mice showed delayed weight loss by
Discussion
There is increasing evidence that inflammatory mechanisms play a role in ALS pathogenesis. There is robust microglial activation in transgenic mouse models as well as human postmortem studies (Hirano, 1996, Hall et al., 1998, Schiffer et al., 1996). IL-1β, tumor necrosis factor-α, and iNOS levels are increased in transgenic mouse models of ALS (Almer et al., 1999, Elliott, 2001, Ghezzi et al., 1998, Li et al., 2000). Inhibition of IL-1β activation slowed disease progression in one transgenic
Acknowledgments
This work was supported in part by grants from Muscular Dystrophy Association and the Amyotrophic Lateral Sclerosis Association and by NIH grants to MFB and MK.
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