Ethyl Pyruvate Rescues Nigrostriatal Dopaminergic Neurons by Regulating Glial Activation in a Mouse Model of Parkinson’s Disease

Abstract

This study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO) and subsequent reactive oxygen species/reactive nitrogen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase-, and/or inducible NO synthase-derived reactive oxygen species/reactive nitrogen species production by activated microglia. Interestingly, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present findings show that EP may inhibit glial-mediated oxidative stress, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson’s disease related to glia-derived oxidative damage.

N-Terminal Truncated UCH-L1 Prevents Parkinson's Disease Associated Damage

“…The sections were immunostained for tyrosine hydroxylase (TH) to specifically detect DA neurons. As we reported previously [49]-[51], immunohistochemical analysis, stereological counts, and densitometric analyses revealed a 60% loss of TH-positive cell bodies in the substantia nigra pars compacta (SNpc) (Fig. 8D-c and E), and a 31% loss in TH-positive fibers in the striatum (STR) (Fig.…”

“…As described previously [49]–[51], mice were administered four i.p. injections of MPTP (20 mg/kg, free base; Sigma-Aldrich) dissolved in PBS at 2 h intervals, and were transcardially perfused and fixed with 4% paraformaldehyde dissolved in 0.1 M phosphate buffer (PB).…”

Interleukin-4 Contributes to Degeneration of Dopamine Neurons in the Lipopolysaccharide-treated Substantia Nigra in vivo

“…In our previous reports, CD11b + -reactive microglia was inhibited by capsaicin in the SN of 1-methy-4-phenylpyridinium (MPP + )-treated rat, resulting in survival of DA neurons [27]. Inhibition of Mac-1 + -, Iba-1 + -, and CD68 + -reactive microglia by ethyl pyruvate [28] and inhibition of CD68 + -reactive microglia by cannabinoid receptor agonists [29] resulted in DA neuron survival in the SN of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In case of LPS-treated rat SN, fluoxetine prevents the degeneration of DA neurons by inhibiting expression of Mac-1 + - and CD68 + -reactive microglia [30].…”

Regulation of pyruvate metabolism and human disease

“…In cultured primary rat neurons, administration of pyruvate prevented Aβ-induced oxidative neuronal death [229, 230]. In a mouse model of Parkinson’s disease, the administration of ethyl pyruvate, an ethyl ester of pyruvate that is hydrolyzed into pyruvate and ethanol, protected substantia nigra neurons from oxidative neurotoxicity, which was attributed to metabolic protection provided by pyruvate metabolism [231]. Additional studies have shown that ethyl pyruvate administration inhibits RNS and ROS damage [232] and protects neurons from peroxide-induced damage [233].…”