Date of Graduation

Spring 5-2012

Level of Access

Open Access

Degree Name

Bachelor of Science

Department or Program

Neuroscience

Number of Pages

66

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopamine (DA) neurons in the substantia nigra. The most effective treatment is DA replacement therapy using the DA precursor L-DOPA, which can unfortunately often result in L-DOPA-induced dyskinesia (LID). Animal studies in hemi-Parkinsonian rats have shown glutamatergic NMDA receptor antagonists to be effective in treating both PD symptoms and LID, however, the cognitive side effects prevent these drugs from passing clinical trials. Upregulation of GLT-1, the primary glutamate transporter that removes glutamate from the synapse, could be an alternative to direct receptor antagonism. The β-lactam antibiotic ceftriaxone has been shown to substantially increase GLT-1 protein expression and activity in the brain without side effects. In Experiment 1 it was found that sub-chronic injections of 100 mg/kg ceftriaxone in unilaterally 6-OHDA-lesioned rats caused a 44% increase in impaired forepaw stepping, a measure of bradykinesia, that lasted at least 30 days after the last ceftriaxone injection. In Experiment 2, sub-chronic injections of 50 mg/kg ceftriaxone resulted in a 41% increase in impaired forepaw stepping that was found to be equivalent to that produced by 10 mg/kg L-DOPA. However unlike ceftriaxone, treatment with L-DOPA resulted in the development of L-DOPA-induced dyskinesia. Ceftriaxone was able to slow the development of LID, but not decrease the expression of pre-established LID. Indicating that the effects of ceftriaxone on forepaw stepping were due to enhanced GLT-1 function, injections of the selective GLT-1 inhibitor, dihydrokainate (DHK) reduced the improvement in stepping produced by ceftriaxone. Collectively, these data indicate that ceftriaxone may be a superior treatment for Parkinson’s disease than L-DOPA.

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