ro13-9904 and Nerve-Degeneration

GFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and successively in different neurological diseases including scrapie, Alzheimer's and Creutzfeld-Jacob diseases. Recently, ceftriaxone a multi-potent β-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded mutated GFAP, similarly to phenytoin sodium, in a cellular model of Alexander's disease and inhibited α-synuclein aggregation protecting PC12 cells from the exposure to 6-hydroxydopamine.. In this study, synchrotron radiation circular dichroism spectroscopy has been used to obtain structural information about the GFAP-ceftriaxone (phenytoin) interactions, while computational methods allowed the identification of the relevant putative binding site of either ceftriaxone or phenytoin on the dimer structure of GFAP, permitting to rationalize the spectroscopic experimental results.. We found that GFAP exhibited enhanced stability upon the addition of two equivalents of each ligands with ceftriaxone imparting a more spontaneous interactions and a more ordered complex system than phenytoin.. SRCD data and MD models indicate a stronger protective effect of ceftriaxone in neurological disorders characterized by an increased production and polymerization of GFAP.. This result, in addition to our previous works in which we documented that ceftriaxone interacts with α-synuclein inhibiting its pathological aggregation and that a cyclical treatment with this molecule in a patient with adult-onset Alexander's disease halted, and partly reversed, the progression of neurodegeneration, suggests the possibility of a chaperone-like effect of ceftriaxone on protein involved in specific neurodegenerative diseases.

Topics: Alexander Disease; alpha-Synuclein; Animals; Astrocytes; Binding Sites; Ceftriaxone; Glial Fibrillary Acidic Protein; Humans; Intermediate Filament Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Nerve Degeneration; PC12 Cells; Phenytoin; Protein Aggregation, Pathological; Rats

Glutamate transporters are responsible for removing glutamate from the extracellular space and have the potential to protect neurons from excitotoxicity. In the present study, the effects of ceftriaxone and (2R, 4R)-APDC (APDC) on the protein expression of GLAST and GLT-1, the rate of glutamate uptake, and neuroprotection were evaluated in a cell culture model of glutamate excitotoxicity.. Mixed neuron/astrocyte cultures were prepared from 1 day old rat pups. Protein levels of GLAST and GLT-1 glutamate transporters were quantified using In-Cell Western techniques after acute or 5-day treatment with either ceftriaxone or APDC. Glutamate uptake was measured using Michaelis-Menten kinetics to evaluate the effects of 5-day treatment with ceftriaxone or APDC. Neuronal cell death in response to a 10-minute 1 mM glutamate challenge was measured following 5-day treatment with either ceftriaxone or APDC.. Five-day treatment with 100 μM ceftriaxone significantly increased both GLAST and GLT-1 protein levels 31.3% and 47.5% above control, respectively, increased the Vmax 29.3%, increased the Km of glutamate uptake 117.9%, and reduced neuronal death 22.0% after a 1 mM glutamate challenge. Five-day treatment with 1 mM APDC significantly increased GLAST protein levels 27.6%, increased the Vmax 92.4%, increased the Km of glutamate transport 118.9%, and decreased neuronal death 36.8% after a 1 mM glutamate challenge.. Chronic treatment with ceftriaxone or APDC provided neuroprotection from glutamate excitotoxicity while increasing GLAST and GLT-1 protein levels and increasing glutamate uptake. These compounds may have therapeutic potential in chronic excitotoxic neurodegenerative diseases.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Ceftriaxone; Cells, Cultured; Coculture Techniques; Excitatory Amino Acid Transporter 1; Glucose Transporter Type 1; Glutamic Acid; Nerve Degeneration; Neurotoxins; Proline; Rats; Rats, Sprague-Dawley; Up-Regulation

Exposure to high altitude is known to cause impairment in cognitive functions in sojourners. The molecular events leading to this behavioral manifestation, however, still remain an enigma. The present study aims at exploring the nature of memory impairment occurring on chronic exposure to hypobaric hypoxia and the possible role of glutamate in mediating it. Increased ionotropic receptor stimulation by glutamate under hypobaric hypoxic conditions could lead to calcium mediated excitotoxic cell death resulting in impaired cognitive functions. Since glutamate is cleared from the synapse by the Glial Glutamate Transporter, upregulation of the transporter can be a good strategy in preventing excitotoxic cell death. Considering previous reports on upregulation of the expression of Glial Glutamate Transporter on ceftriaxone administration, the therapeutic potential of ceftriaxone in ameliorating hypobaric hypoxia induced memory impairment was investigated in male Sprague Dawley rats. Exposure to hypobaric hypoxia equivalent to an altitude of 7600 m for 14 days lead to oxidative stress, chromatin condensation and neuronal degeneration in the hippocampus. This was accompanied by delayed memory retrieval as evident from increased latency and pathlength in Morris Water Maze. Administration of ceftriaxone at a dose of 200 mg/kg for 7 days and 14 days during the exposure on the other hand improved the performance of rats in the water maze along with decreased oxidative stress and enhanced neuronal survival when compared to hypoxic group without drug administration. An increased expression of Glial Glutamate Transporter was also observed following drug administration indicating faster clearance of glutamate from the synapse. The present study not only brings to light the effect of longer duration of exposure to hypobaric hypoxia on the memory functions, but also indicates the pivotal role played by glutamate in mediating excitotoxic neuronal degeneration at high altitude. The therapeutic potential of ceftriaxone in providing neuroprotection in excitotoxic conditions by increasing Glial Glutamate Transporter expression and thereby enhancing glutamate uptake from the synapse has also been explored.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Chromatin; Chronic Disease; Excitatory Amino Acid Transporter 2; Glutamic Acid; Glutathione; Hippocampus; Hypoxia, Brain; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Maze Learning; Memory; Memory Disorders; Nerve Degeneration; Neurons; Neurotoxins; Oxidative Stress; Rats; Rats, Sprague-Dawley; Space Perception

Lyme disease is an infectious disease caused by the spirochete Borrelia burgdorferi. The course of the disease is divided into three stages, the second of which may include various types of peripheral nervous system disturbances. We report the case of a patient with persistent deficits caused by the prevalent involvement of the sciatic nerve, confirmed by electrophysiological and neuropathological findings. The most significant bioptic results were axonal degeneration and perivascular inflammation. Damage to a single peripheral nerve as the dominant clinical expression during the course of Lyme disease is an unusual finding that has been rarely described in the literature.

Topics: Aged; Biopsy; Ceftriaxone; Cephalosporins; Electromyography; Female; Humans; Lyme Disease; Nerve Degeneration; Neuritis; Sciatic Nerve; Tomography, X-Ray Computed