Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model

Tanya Chotibut, Richard W. Davis, Jennifer C. Arnold, Zachary Frenchek, Shawn Gurwara, Vimala Bondada, James W. Geddes, Michael Francis Salvatore

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

Excess glutamatergic neurotransmission may contribute to excitotoxic loss of nigrostriatal neurons in Parkinson's disease (PD). Here, we determined if increasing glutamate uptake could reduce the extent of tyrosine hydroxylase (TH) loss in PD progression. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in central nervous system and may attenuate adverse behavioral or neurobiological function in other neurodegenerative disease models. In association with >80 % TH loss, we observed a significant decrease in glutamate uptake in the established 6-hydroxydopamine (6-OHDA) PD model. Ceftriaxone (200 mg/kg, i.p.) increased striatal glutamate uptake with ≥5 consecutive days of injection in nonlesioned rats and lasted out to 14 days postinjection, a time beyond that required for 6-OHDA to produce >70 % TH loss (∼9 days). When ceftriaxone was given at the time of 6-OHDA, TH loss was ∼57 % compared to ∼85 % in temporally matched vehicle-injected controls and amphetamine-induced rotation was reduced about 2-fold. This attenuation of TH loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. These results reveal that glutamate uptake can be targeted in a PD model, decrease the rate of TH loss in a calcium-dependent manner, and attenuate locomotor behavior associated with 6-OHDA lesion. Given that detection of reliable PD markers will eventually be employed in susceptible populations, our results give credence to the possibility that increasing glutamate uptake may prolong the time period before locomotor impairment occurs.

Original languageEnglish
Pages (from-to)1282-1292
Number of pages11
JournalMolecular Neurobiology
Volume49
Issue number3
DOIs
StatePublished - 1 Jan 2014

Fingerprint

Corpus Striatum
Ceftriaxone
Oxidopamine
Tyrosine 3-Monooxygenase
Glutamic Acid
Parkinson Disease
Amino Acid Transport System X-AG
Calcium
Neurons
beta-Lactams
Amphetamine
Synaptic Transmission
Neurodegenerative Diseases
Serine
Disease Progression
Central Nervous System
Phosphorylation
Anti-Bacterial Agents
Injections
Population

Keywords

  • 6-OHDA
  • Ceftriaxone
  • GLT-1
  • Neuroprotection
  • Parkinson's disease
  • Tyrosine hydroxylase

Cite this

Chotibut, Tanya ; Davis, Richard W. ; Arnold, Jennifer C. ; Frenchek, Zachary ; Gurwara, Shawn ; Bondada, Vimala ; Geddes, James W. ; Salvatore, Michael Francis. / Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model. In: Molecular Neurobiology. 2014 ; Vol. 49, No. 3. pp. 1282-1292.
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abstract = "Excess glutamatergic neurotransmission may contribute to excitotoxic loss of nigrostriatal neurons in Parkinson's disease (PD). Here, we determined if increasing glutamate uptake could reduce the extent of tyrosine hydroxylase (TH) loss in PD progression. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in central nervous system and may attenuate adverse behavioral or neurobiological function in other neurodegenerative disease models. In association with >80 {\%} TH loss, we observed a significant decrease in glutamate uptake in the established 6-hydroxydopamine (6-OHDA) PD model. Ceftriaxone (200 mg/kg, i.p.) increased striatal glutamate uptake with ≥5 consecutive days of injection in nonlesioned rats and lasted out to 14 days postinjection, a time beyond that required for 6-OHDA to produce >70 {\%} TH loss (∼9 days). When ceftriaxone was given at the time of 6-OHDA, TH loss was ∼57 {\%} compared to ∼85 {\%} in temporally matched vehicle-injected controls and amphetamine-induced rotation was reduced about 2-fold. This attenuation of TH loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. These results reveal that glutamate uptake can be targeted in a PD model, decrease the rate of TH loss in a calcium-dependent manner, and attenuate locomotor behavior associated with 6-OHDA lesion. Given that detection of reliable PD markers will eventually be employed in susceptible populations, our results give credence to the possibility that increasing glutamate uptake may prolong the time period before locomotor impairment occurs.",
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Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model. / Chotibut, Tanya; Davis, Richard W.; Arnold, Jennifer C.; Frenchek, Zachary; Gurwara, Shawn; Bondada, Vimala; Geddes, James W.; Salvatore, Michael Francis.

In: Molecular Neurobiology, Vol. 49, No. 3, 01.01.2014, p. 1282-1292.

Research output: Contribution to journalArticleResearchpeer-review

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