Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model

Tanya Chotibut, Samantha Meadows, Ella A. Kasanga, Tamara McInnis, Mark A. Cantu, Christopher Bishop, Michael Francis Salvatore

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss.

Original languageEnglish
Pages (from-to)1547-1556
Number of pages10
JournalMovement Disorders
Volume32
Issue number11
DOIs
StatePublished - 1 Nov 2017

Fingerprint

Dihydroxyphenylalanine
Ceftriaxone
Oxidopamine
Dyskinesias
Parkinson Disease
Corpus Striatum
Glutamic Acid
Tyrosine 3-Monooxygenase
Amino Acid Transport System X-AG
Glutamate Receptors
Synaptic Transmission
Therapeutics

Keywords

  • GLT-1
  • Parkinson's disease
  • ceftriaxone
  • dyskinesia
  • glutamate
  • l-dopa

Cite this

Chotibut, Tanya ; Meadows, Samantha ; Kasanga, Ella A. ; McInnis, Tamara ; Cantu, Mark A. ; Bishop, Christopher ; Salvatore, Michael Francis. / Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. In: Movement Disorders. 2017 ; Vol. 32, No. 11. pp. 1547-1556.
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title = "Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model",
abstract = "Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss.",
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Chotibut, T, Meadows, S, Kasanga, EA, McInnis, T, Cantu, MA, Bishop, C & Salvatore, MF 2017, 'Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model', Movement Disorders, vol. 32, no. 11, pp. 1547-1556. https://doi.org/10.1002/mds.27077

Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. / Chotibut, Tanya; Meadows, Samantha; Kasanga, Ella A.; McInnis, Tamara; Cantu, Mark A.; Bishop, Christopher; Salvatore, Michael Francis.

In: Movement Disorders, Vol. 32, No. 11, 01.11.2017, p. 1547-1556.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model

AU - Chotibut, Tanya

AU - Meadows, Samantha

AU - Kasanga, Ella A.

AU - McInnis, Tamara

AU - Cantu, Mark A.

AU - Bishop, Christopher

AU - Salvatore, Michael Francis

PY - 2017/11/1

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N2 - Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss.

AB - Background: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa–induced dyskinesia in an established dyskinesia model. Methods: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). Results: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. Conclusions: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss.

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Chotibut T, Meadows S, Kasanga EA, McInnis T, Cantu MA, Bishop C et al. Ceftriaxone reduces L-dopa–induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. Movement Disorders. 2017 Nov 1;32(11):1547-1556. https://doi.org/10.1002/mds.27077