Abstract Title

Ceftriaxone, a Beta-Lactam Antibiotic, Reduces the Severity of L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

RAD Assignment Number

1804

Presenter Name

Ella A. Kasanga

Abstract

Purpose: Levodopa (L-DOPA) therapy remains the most pharmacologically used agent for the management of Parkinson’s disease (PD). However, chronic treatment with L-DOPA leads to debilitating dyskinesias in 50% of Parkinson’s disease patients after 5 years and ~90% after 10 years. Delineating the mechanisms of L-DOPA-induced dyskinesia (LID) is therefore a major priority for alleviating this debilitating side effect of L-DOPA. There is evidence for increased glutamate signaling in LID and in PD. However, glutamate receptor antagonists in the PD patient have achieved mixed clinical outcomes with untoward side effects. Therefore, an alternate intervention targeting the elevated glutamatergic signaling could prove useful. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a transporter that plays a major role in glutamate clearance in the central nervous system. We have recently shown that ceftriaxone when given at the time of 6-hydroxydopamine (6-OHDA) injection resulted in an attenuation of tyrosine hydroxylase (TH) loss, an increase in GLT-1 expression and reduced serine-19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. In this study, we determined if ceftriaxone therapy initiated 7 days after 6-OHDA, but prior to L-DOPA, could reduce L-DOPA-induced abnormal involuntary movements (AIMS) in an established L-DOPA-induced dyskinesia model.

Methods: Ceftriaxone (200 mg/kg, i.p., once daily for 7 consecutive days) was initiated 7 days post-6-OHDA lesion (days 7-13) and then continued every other week (days 21-27, 35-38) until the end of the study (day 38 post-lesion, 20 consecutive days of L-DOPA).

Results: Preliminary results show reduced AIMs at the time points 1, 4 and 7 days after the initiation of L-DOPA treatment upon the administration of ceftriaxone with a significant reduction (p<0.01) observed at 7 days. We also observed a reduction in amphetamine-induced rotations (ipsilateral to the lesion) in the ceftriaxone treated group on day 14 while an increase in the rotations were observed in the vehicle group, suggesting that ceftriaxone mitigated lesion severity in conjunction with reducing LID.

Conclusions: Intermittent delivery of a ceftriaxone regimen prior to and after L-DOPA may reduce LID severity, possibly in conjunction with a reduction in nigrostriatal lesion severity during the time course of ceftriaxone administration.

Research Area

Neuroscience

Presentation Type

Poster

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Ceftriaxone, a Beta-Lactam Antibiotic, Reduces the Severity of L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson’s Disease

Purpose: Levodopa (L-DOPA) therapy remains the most pharmacologically used agent for the management of Parkinson’s disease (PD). However, chronic treatment with L-DOPA leads to debilitating dyskinesias in 50% of Parkinson’s disease patients after 5 years and ~90% after 10 years. Delineating the mechanisms of L-DOPA-induced dyskinesia (LID) is therefore a major priority for alleviating this debilitating side effect of L-DOPA. There is evidence for increased glutamate signaling in LID and in PD. However, glutamate receptor antagonists in the PD patient have achieved mixed clinical outcomes with untoward side effects. Therefore, an alternate intervention targeting the elevated glutamatergic signaling could prove useful. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a transporter that plays a major role in glutamate clearance in the central nervous system. We have recently shown that ceftriaxone when given at the time of 6-hydroxydopamine (6-OHDA) injection resulted in an attenuation of tyrosine hydroxylase (TH) loss, an increase in GLT-1 expression and reduced serine-19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. In this study, we determined if ceftriaxone therapy initiated 7 days after 6-OHDA, but prior to L-DOPA, could reduce L-DOPA-induced abnormal involuntary movements (AIMS) in an established L-DOPA-induced dyskinesia model.

Methods: Ceftriaxone (200 mg/kg, i.p., once daily for 7 consecutive days) was initiated 7 days post-6-OHDA lesion (days 7-13) and then continued every other week (days 21-27, 35-38) until the end of the study (day 38 post-lesion, 20 consecutive days of L-DOPA).

Results: Preliminary results show reduced AIMs at the time points 1, 4 and 7 days after the initiation of L-DOPA treatment upon the administration of ceftriaxone with a significant reduction (p<0.01) observed at 7 days. We also observed a reduction in amphetamine-induced rotations (ipsilateral to the lesion) in the ceftriaxone treated group on day 14 while an increase in the rotations were observed in the vehicle group, suggesting that ceftriaxone mitigated lesion severity in conjunction with reducing LID.

Conclusions: Intermittent delivery of a ceftriaxone regimen prior to and after L-DOPA may reduce LID severity, possibly in conjunction with a reduction in nigrostriatal lesion severity during the time course of ceftriaxone administration.