levetiracetam and Parkinsonian-Disorders

Epilepsy with the main symptom of amnesia is known as transient epileptic amnesia (TEA). Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. The concept that Lewy body disease includes Parkinson's disease with dementia and dementia with Lewy bodies was proposed in the 2005 revision of the Clinical Diagnostic Criteria. Here, we describe a woman with cognitive impairment, olfactory dysfunction, and reduced

Topics: 3-Iodobenzylguanidine; Aged; Amnesia; Anticonvulsants; Cognition Disorders; Electroencephalography; Female; Hallucinations; Humans; Levetiracetam; Lewy Body Disease; Myocardial Perfusion Imaging; Parkinsonian Disorders; Piracetam; Seizures; Tomography, Emission-Computed, Single-Photon

Astrocytes but not neurons express cystine/glutamate exchange transporter (xCT), which takes up cystine, and consequently supplies the substrate for GSH synthesis in neurons. It is recognized that GSH synthesis in neurons is dependent on the expression of xCT in astrocytes. Previous studies reported that levetiracetam (LEV), an anti-epileptic drug, increased xCT expression in vivo. The purpose of this study was to examine neuroprotective effects of LEV in parkinsonian models and demonstrate xCT in astrocytes as a target of neuroprotection against dopaminergic neurodegeneration. We identified striatal astrocytes cultured with LEV showed significant increase in xCT expression and GSH levels. Preincubation of primary cultured mesencephalic dopamine neurons with conditioned media from LEV-treated astrocytes protected against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. These protective effects were canceled by xCT inhibitor. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-OHDA-lesioned parkinsonian mice was significantly abrogated by repeated injections of LEV. Treatment with LEV significantly increased the expression of xCT in striatal astrocytes in the hemi-parkinsonian mice. In conclusion, LEV exerts neuroprotective effects against neurodegeneration via up-regulation of xCT and GSH in astrocytes. Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons. Glutathione (GSH) is the most potent intrinsic antioxidant. Since extracellular cysteine is readily oxidized to form cystine, cystine transport mechanisms are essential to provide cells with cysteine. Cystine uptake is mediated by cystine/glutamate exchange transporter (xCT), expressed primarily on astrocytes, but not on neurons. Astrocytes take up cystine via xCT and reduce it to cysteine to supply cysteine, the substrate for GSH synthesis in neurons. This study demonstrated that levetiracetam (LEV), an anti-epileptic drug, increased GSH in/from astrocytes via xCT up-regulation. GSH derived from astrocytes protects dopamine neurons against neurotoxicity induced by dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons.

Topics: Amino Acid Transport System y+; Animals; Astrocytes; Cells, Cultured; Drug Delivery Systems; Female; Levetiracetam; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; Parkinsonian Disorders; Piracetam; Pregnancy; Rats; Rats, Sprague-Dawley

Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anticonvulsants; Antiparkinson Agents; Callithrix; Dopamine Agents; Drug Synergism; Drug Therapy, Combination; Female; Indoles; Levetiracetam; Levodopa; Male; Parkinsonian Disorders; Piracetam