The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice.
[en] Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Because accompanying inflammation may interact with and promote neurodegeneration, anti-inflammatory treatment strategies are being evaluated. Because peroxisome proliferator-activated receptor gamma (PPARgamma) agonists act as potent anti-inflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPARgamma agonist pioglitazone (Pio). Pio-treated transgenic mice revealed improved muscle strength and body weight, exhibited a delayed disease onset, and survived significantly longer than nontreated SOD1-G93A mice. Quantification of motor neurons of the spinal cord at day 90 revealed complete neuroprotection by Pio, whereas nontreated SOD1-G93A mice had lost 30% of motor neurons. This was paralleled by preservation of the median fiber diameter of the quadriceps muscle, indicating not only morphological but also functional protection of motor neurons by Pio. Activated microglia were significantly reduced at sites of neurodegeneration in Pio-treated SOD1-G93A mice, as were the protein levels of cyclooxygenase 2 and inducible nitric oxide synthase. Interestingly, mRNA levels of the suppressor of cytokine signaling 1 and 3 genes were increased by Pio, whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected.
Disciplines :
Neurology
Author, co-author :
Schütz, Burkhard; Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Reimann, Jens; Laboratory of Neuroinflammation, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Dumitrescu-Ozimek, Lucia; Laboratory of Neuroinflammation, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Kappes-Horn, Karin; Laboratory of Neuroinflammation, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Landreth, Gary E; Alzheimer Research Laboratory, Department of Neuroscience, Case Western Reserve University, Cleveland, OH 44106-4928, United States
Schürmann, Britta; Laboratory of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Zimmer, Andreas; Laboratory of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
HENEKA, Michael ; Laboratory of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany ; Department of Neurology, University of Münster, 48149 Münster, Germany
External co-authors :
yes
Language :
English
Title :
The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice.
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