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Neurodegeneration. models of Parkinson's Disease. mechanisms of cell death. synaptic vesicles and neurotransmitter transporters as modulators of neurotoxin damageThe goal of our research is to gain an understanding of neurodegeneration. particularly of the nigrostriatal dopaminergic neurons that are destroyed in Parkinson's disease. and to develop pharmacological strategies to prevent cell death. Present research focuses on the roles of mitochondria. synaptic vesicles. the neurotransmitter transporters and the neurotransmitter dopamine in neurodegeneration. We have found that vesicles within dopaminergic neurons may act as storage sites for the dopaminergic neurotoxin. 1-methyl-4-phenylpyridinium. thus reducing its toxicity. Conversely. we have discovered that when vesicles are disrupted and dopamine is displaced into the cytosol. especially under conditions of a metabolic stress such as that created by mitochondrial inhibitors. neuronal damage is intensified. This enhanced toxicity may derive from an increase in dopamine oxidation products within the cytosol. Additionally. we have observed a rapid loss of vesicle function in vivo following exposure to neurotoxins. It is not known if this phenomenon reflects a primary step in neurodegeneration or is a consequence of an oxidative stress. but demonstrates the early disruption of a cellular organelle critical for maintaining neuronal activity. In vitro cell culture models. isolated vesicle preparations and in vivo studies with brain infusion and microdialysis techniques are used in our research. A current research aim is to examine whether other neurotoxins may be sequestered into the vesicles. Other aims will investigate the role of dopamine and its oxidation products in neurodegeneration and assess various pharmacological agents for their ability to provide protection against cell death. Additionally. we will examine a number of drugs or environmental substances that disrupt vesicular function and displace dopamine from vesicles for their propensity to exacerbate damage during toxic insult and stressful conditions. Selected PublicationsSonsalla PK, Zeevalk GD, German DC. (2008) Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson's disease. Parkinsonism Relat Disord. Jun 24. [Epub ahead of print] Rocha MA, Crockett DP, Wong LY, Richardson JR, Sonsalla PK. (2008) Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions. J Neurochem. Apr 17. [Epub ahead of print] Meredith GE, Sonsalla PK, Chesselet MF. (2008) Animal models of Parkinson's disease progression. Acta Neuropathol. 115(4):385-98. Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A. (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation.Prog Neurobiol. 83(5):310-31. Moy LY, Wang SP, Sonsalla PK. (2007) Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the dopamine transporter. J Pharmacol Exp Ther. 320(2):747-56. Alfinito. P.D.. Wang. S.P.. Manzino. L.. Rijhsinghani. S.. Zeevalk. G.D.. and Sonsalla. P.K. (2003) Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum. respectively. J. Neurosci. 23: 10982 - 10987. Zeevalk. G.D.. Manzino. L.. and Sonsalla. P.K. (2002) Protection of malonate-induced GABA but not dopamine loss by GABA transporter blockade in rat striatum. Exp. Neurol. 176:193-202. Cho. J.. Manzino. L.. Sonsalla. P.K.. Duke. D. and West. M.O. (2002) Fragmented clustering of neurons phasically related to sensorimotor activity in the striatum of hemiparkinsonian rats: Evidence of lasting. altered responsiveness to corticostriatal input. J. Comp. Neurol. 452:24-37. Chen. J-F.. Steyn. S.. Staal. R.. Petzer. J.P.. Xu. K.. Castagnoli. K.. Sonsalla. P.K.. Castagnoli. Jr.. N. and Schwarzschild. M.A. (2002) 2-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of MAO inhibition and A2a receptor antagonism. J. Biological. Chem. (published. JPC Papers in Press. July 18. 2002). Chen. J.-F.. Xu. K.. Petzer. J.P.. Staal. R.. Xu. Y.-H.. Beilstein. M.. Sonsalla. P.K.. Castognoli. K.. Castognoli Jr.. N. and Schwarzschild (2001) Neuroprotection by caffeine and A2a adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 21: R143-R149. Zeevalk. G.D.. Bernard. L.P.. Manzino. L. and Sonsalla. P.K. (2001) Differenctial sensitivity of mesenceiphalic neurons to inhibition of phosphatase 2A. J. Pharmacol. Exptl. Therap. 298:925-933. Staal. R.G.W.. Yang. J.-M.. Hait. W.N. and Sonsalla. P.K. (2001) Interactions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium and other compounds with P-glycoprotein: Relevance to toxicity of 11-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Brain Research 910:116-125. Gluck. Martin R.. Jayatilleke. E.. Moy. L.Y.. Hogan. K.A.. Manzino. L. and Sonsalla. P.K. (2001) Increases in lipid and protein oxidative markers in mouse brain following methamphetamine treatment J. Neurochem. 79: 152- 160. |
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