The Oral Antidiabetic Pioglitazone Protects from Neurodegeneration and Amyotrophic Lateral Sclerosis-Like Symptoms in Superoxide Dismutase-G93A Transgenic Mice

Abstract

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 ␥ (PPAR␥) agonists act as potent antiinflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPAR␥ 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.

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

“…Second, A2a receptor antagonists protect purified motor neurons from insult indicating the lack of necessity of nonmotor neurons and glial cells in the biological effect. Thus, although ALS is increasingly being viewed a disorder that involves the participation of multiple cell types (i.e., astrocytes, muscle, microglia), the present results highlight motor neuron-specific processes (Clem-ent et al, 2003;Dupuis et al, 2003Dupuis et al, , 2004Barbeito et al, 2004;Pehar et al, 2004;Cassina et al, 2005;Schutz et al, 2005).…”

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

“…First, the possibility cannot be ruled out that the brain utilises more of a fuel other than glucose, such as lactate of peripheral origin [37]. Second, pioglitazone treatment may be protective by limiting the highest rates of regional glucose oxidative metabolism and the concomitant oxidative stress [14,32,38,39], in association with the benefits derived from the attenuation of inflammation [5]. Finally, pioglitazone can induce the expression of proteins related to the stress response [40] and mitochondrial membrane hyperpolarisation that can safeguard the cells against an excessive metabolic rate [9].…”

“…The finding that thiazolidinediones are potent inhibitors of inflammation [3][4][5] has prompted several clinical trials testing the effects of thiazolidinediones in neurological diseases such as Alzheimer's disease and multiple sclerosis, in which inflammation contributes to pathogenesis [6]. The antiinflammatory properties of pioglitazone in the brain have also been shown in murine models of acute [7] and chronic [8] inflammation, when this thiazolidinedione was administered to the animals orally.…”

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

“…On the other hand, PPAR␥ agonists induce mt biogenesis and oxidative metabolism, 15,16 and protect against neurodegeneration and amyotrophic lateral sclerosis by increasing mt function. 17,18 Our previous study showed that Aldo-induced renal proximal tubular epithelial cell injury was mediated by mt reactive oxygen species (ROS). 6 We postulated that the same mediator (ie, mt ROS) may contribute to Aldo-induced podocyte injury and may serve as a therapeutic target of PPAR␥ agonists in renal diseases.…”