Parkinson's disease (PD) is a progressive neurologic disorder characterized by rigidity, bradykinesia? and tremor. The mainstay of treatment is dopamine (DA) replacement therapy with L-dopa. Disabling side? effects siich as dyskinesia and motor fluctuations often undermine L-dopa treatment and have prompted the? need to identify non-dopaminergic drug targets. In the basal ganglia, DA neuronal loss leads to hyperactivity? of the subthalamic nucleus, which provides an increased glutamatergic excitatory drive onto the internal part? of the globus pallidus and substantia nigra pars reticulata. Strategies to counteract glutamatergic? hyperactivity can provide alternatives to conventional dopaminergic therapies. It has been observed that? typical antipsychotic drugs (APD), which are potent DA D2 antagonists, have parkinsdnism side effect? whereas atypical APD that exhibit a high 5-HT2A:DA D2 receptor affinities ratio, are less prone to induce? parkinsonism. Animal studies showed that haloperidol-induced catalepsy was reduced by 5-HT2A receptor? antagonists. Limited success of clinical trials involving 5-HT2 antagonists could be attributed to the relatively? nonspecific 5-HT effects of the agents used or lack of information on the serotonergic drug targets impacted? in PD. Cortieo-striatal and pallido-striatal neurons are a major source of 5-HT2A receptor binding in the? striatum. This proposal will test the hypothesis that 5-HT2A receptor antagonists acting at cortico-striatal? terminals may be beneficial in restoring motor function in parkinsonism by decreasing glutamate release? from cortico-striatal neurons.
The specific aims proposed are 1)To determine the impact of 1-methyl-4-? phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hypokinesia on serotonergic markers in mice: 2) To? examine the effect of treatment with 5-HT2A, 5-HT2C and mixed 5-HT2A/2C receptor antagonists on MPTPinduced? motor deficits 3)To determine if treatment with 5-HT2A receptor antagonists will decrease striatal? extracellular glutamate levels and alter the functional activity of striatal neurons of MPTP-treated mice.
|Charlton, Clivel G (2014) Methylation reactions at dopaminergic nerve endings, serving as biological off-switches in managing dopaminergic functions. Neural Regen Res 9:1110-1|
|Dhanushkodi, Nisha R; Mohankumar, Vidyarani; Raju, Ramaswamy (2012) Sindbis virus induced phosphorylation of IRF3 in human embryonic kidney cells is not dependent on mTOR. Innate Immun 18:325-32|
|Li, Zhu; Chadalapaka, Gayathri; Ramesh, Aramandla et al. (2012) PAH particles perturb prenatal processes and phenotypes: protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following in utero exposure to inhaled benzo(a)pyrene. Toxicol Sci 125:233-47|
|Jules, G E; Pratap, S; Ramesh, A et al. (2012) In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life. Toxicology 295:56-67|
|King, Jennifer M; Muthian, Gladson; Mackey, Veronica et al. (2011) L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease. Life Sci 89:638-43|
|Kawai, Yumiko; Garduño, Lakisha; Theodore, Melanie et al. (2011) Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 286:7629-40|
|Dhanushkodi, Nisha R; Mohankumar, Vidyarani; Pokkali, Supriya et al. (2011) Lipopolysaccharide inhibits Sindbis virus-induced IP-10 release in human peripheral blood mononuclear cells. Viral Immunol 24:237-43|
|Halder, Sunil K; Goodwin, J Shawn; Al-Hendy, Ayman (2011) 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 96:E754-62|
|Mittal, Mukul K; Singh, Kshipra; Misra, Smita et al. (2011) SLUG-induced elevation of D1 cyclin in breast cancer cells through the inhibition of its ubiquitination. J Biol Chem 286:469-79|
|Ansah, Twum A; Ferguson, Marcus C; Nayyar, Tultul (2011) The 5-HT(2A) Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate. Front Syst Neurosci 5:48|
Showing the most recent 10 out of 64 publications