[olsen]

The β-lactam antibiotic ceftriaxone as a treatment for the symptoms of Parkinson’s disease and L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.
Caroline B. Neville, Bates Cellege


Department or Program
Neuroscience

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.
Recommended Citation
Neville, Caroline B., "The β-lactam antibiotic ceftriaxone as a treatment for the symptoms of Parkinson’s disease and L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats." (2012). Honors Theses. Paper 38.
http://scarab.bates.edu/honorstheses/38

[mark f]

Neuroscience. 2010 Sep 15;169(4):1888-900. Epub 2010 Jun 11.
Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders.
Ramos KM, Lewis MT, Morgan KN, Crysdale NY, Kroll JL, Taylor FR, Harrison JA, Sloane EM, Maier SF, Watkins LR.
SourceDepartment of Psychology and Neuroscience, Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA. ]

Abstract
Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.

[olsen]

hmmmm. wonder if it would be beneficial to utilize one of the durgs within this class for suspected infections (ie urinary tract or upper respiratory)? We recently requested Keflex (not knowing this info) for an infection. I wanted to stay away from antibiotics which work via the acetylcholine system. Seems many of the antibiotics for gram negative bacteria do impact that system.

cannot say we noticed any great improvements other than amelioration of the infection.

[lurkingforacure]

I read they are currently using this in a clinical trial for ALS. Apparently they tried it before, it didn't work like hoped, they waited a bit, and are re-trying it again.

Forums are valuable sources of information. I visited an ALS forum to get a "feel" for how patients viewed this trial, and the drug, and got mixed results. One poster was quite cynical and echoed what many say about PD research: same old, same old, this is just another example of science trying new uses for drugs that have expired patents or re-working drugs to extend the patent. One astute guy noted, though, that until they mimic what happens in real life in the lab, nothing will change...his point was that they always pre-treat the animal with the drug BEFORE giving it the disease at hand, which never happens in life. If we'd known we were going to get slammed with PD, we'd have been smoking cigarettes, eating wheels of MAO-inhibiting cheese, raising that cholesterol to the heavens, and soaking in the sun. But no one does, so why they keep designing trials to deliver the drug first and then induce the disease second is beyond me...surely not $$$$?