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Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease
Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia
Department of Pathology, Faculty of Medicine, University of Latvia, Riga, Latvia
Latvian Institute of Organic Synthesis, Riga, Latvia
Department of Pathology and Laboratory of Medicine and Neurology, University of California Los Angeles, Los Angeles, CA, USA
* Author to whom correspondence should be addressed.
Received: 20 September 2010; in revised form: 22 October 2010 / Accepted: 27 October 2010 / Published: 9 November 2010
Abstract: Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson’s disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6‑OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.
Keywords: Parkinson’s disease; 6-OHDA model; neuroimmunological biomarkers; mildronate; small molecule
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Klusa, V.Z.; Isajevs, S.; Svirina, D.; Pupure, J.; Beitnere, U.; Rumaks, J.; Svirskis, S.; Jansone, B.; Dzirkale, Z.; Muceniece, R.; Kalvinsh, I.; Vinters, H.V. Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease. Int. J. Mol. Sci. 2010, 11, 4465-4487.
Klusa VZ, Isajevs S, Svirina D, Pupure J, Beitnere U, Rumaks J, Svirskis S, Jansone B, Dzirkale Z, Muceniece R, Kalvinsh I, Vinters HV. Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease. International Journal of Molecular Sciences. 2010; 11(11):4465-4487.
Klusa, Vija Z.; Isajevs, Sergejs; Svirina, Darja; Pupure, Jolanta; Beitnere, Ulrika; Rumaks, Juris; Svirskis, Simons; Jansone, Baiba; Dzirkale, Zane; Muceniece, Ruta; Kalvinsh, Ivars; Vinters, Harry V. 2010. "Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease." Int. J. Mol. Sci. 11, no. 11: 4465-4487.