A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity.

Adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the experimental pharmacological therapy for Parkinson's disease (PD). Moreover, it has been postulated that A2A adenosine receptor antagonists exert neuroprotective effects in experimental models of PD and progressive supranuclear palsy (PSP). Interestingly, in both these pathological conditions a deficit of mitochondrial complex I has been found. Thus, utilizing extracellular and intracellular recordings from corticostriatal brain slices, we have tested the possible neuroprotective action of two A2A receptor antagonists, ST1535 and ZM241385, on the irreversible electrophysiological effects induced by the acute application of rotenone, a pesticide acting as a selective inhibitor of mitochondrial complex I activity. Both these antagonists reduced the rotenone-induced loss of corticostriatal field potential amplitude as well as the membrane depolarization caused by this toxin on striatal spiny neurons. The use of A2A receptor antagonists might represent a promising neuroprotective strategy in basal ganglia disorders involving a deficit of mitochondrial complex I activity.

Levetiracetam in newly diagnosed late-onset post-stroke seizures: a prospective observational study.

Levetiracetam (LEV) monotherapy was investigated in 35 patients (pts) (16M/19F, 71.9+/-7.3 years of age) with late-onset post-stroke seizures (i.e. seizures occurring at least 2 weeks after an ischemic stroke) in a prospective open-label study. Overall, 27 pts (77.1%) achieved a condition of seizure freedom (defined as 1 year without seizures): 19 (54.3%) at a daily LEV dose of 1000mg, 7 (20.0%) at 1500mg, 1 (2.8%) at 2000mg. Four pts (11.4%) discontinued the drug because of intolerable side effects (drowsiness associated to gait disturbance in 1 pt, and aggressive behaviour in the remaining 3 pts); 3 pts were unresponsive at a dose of 3000mg, and 1 pt was lost at follow-up. These observations suggest that LEV exhibits safety and efficacy profiles which make it an optimal candidate as a first-choice drug against post-stroke seizures.

Electrophysiology and pharmacology of striatal neuronal dysfunction induced by mitochondrial complex I inhibition.

Reduced activity of the mitochondrial respiratory chain and in particular of complex I is implicated not only in the etiology of Parkinson's disease but also in other forms of parkinsonism in which striatal neurodegeneration occurs, such as progressive supranuclear palsy. The pesticide rotenone inhibits mitochondrial complex I and reproduces features of these basal ganglia neurological disorders in animal models. We have characterized the electrophysiological effects of rotenone in the striatum as well as potential neuroprotective strategies to counteract the detrimental effects of this neurotoxin. We found that rotenone causes a dose-dependent and irreversible loss of the corticostriatal field potential amplitude, which was related to the development of a membrane depolarization/inward current in striatal spiny neurons, coupled to an increased release of both excitatory amino acids and dopamine (DA). In particular, we have investigated whether glutamate, DA, and GABA systems might represent possible targets for neuroprotection against rotenone-induced striatal neuronal dysfunction. Interestingly, whereas modulation of glutamatergic transmission was not neuroprotective, blockade of D(2)-like but not D(1)-like DA receptors significantly reduced the rotenone-induced effects via a GABA-mediated mechanism. In addition, because antiepileptic drugs (AEDs) modulate multiple transmitter systems, we have analyzed the possible neuroprotective effects of some AEDs against rotenone. We found that carbamazepine, unlike other tested AEDs, exerts a potent neuroprotective action against rotenone-induced striatal neuronal dysfunction. This neuroprotection was observed at therapeutically relevant concentrations requiring endogenous GABA. Differential targeting of GABAergic transmission may represent a possible therapeutic strategy against basal ganglia neurodegenerative disorders involving mitochondrial complex I dysfunction.