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In the hippocampal formation many neuromodulators are possibly implied in the synaptic plasticity such as the long-term potentiation (LTP) induced by high-frequency stimulation (HFS) of afferent fibers. We investigated the involvement of locally synthesized neural 17β-estradiol (nE(2)) in the induction of HFS-LTP in hippocampal slices from male rats by stimulating the Schaffer collateral fibers and recording the evoked field excitatory postsynaptic potential (fEPSP) in the CA1 region. We demonstrated that either the blockade of nE(2) synthesis by the aromatase inhibitor letrozole, or the antagonism of E(2) receptors (ERs) by ICI 182,780 did not prevent the induction of HFS-LTP, but reduced its amplitude by ∼60%, without influencing its maintenance. Moreover, letrozole and ICI 182,780 did not affect the first short-term post-tetanic component of LTP and the paired-pulse facilitation (PPF). These findings demonstrate that nE(2) plays an important role in the induction phase of HFS-dependent LTP. Since the basal responses were not affected by the blocking agents, we suggest that the synthesis of nE(2) is induced or enhanced by HFS through aromatase activation. In this context, the local production of nE(2) seems to be a very effective mechanism to modulate the amplitude of LTP., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.) more...

3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) have been shown to protect against ischemic stroke by mechanisms that are independent of lowering serum cholesterol levels. In this study we investigated the potential neuroprotective effect of a single i.v. treatment with four increasing doses of pravastatin on permanent occlusion of middle cerebral artery (MCAo) in spontaneously hypertensive rats. Pravastatin was given 10 min after MCAo and its effect was determined 24 h later. Treatment results were evaluated in terms of infarct volume, homolateral hemisphere oedema, glial fibrillary acid (GFAP), vimentin (Vim) and endothelial NO synthase (eNOS) immunoreactivity and TUNEL positivity. Cerebral levels of eNOS were measured by western blot analysis. Pravastatin did not reduce cerebral infarct while it mitigated homolateral hemisphere oedema in a dose-dependent manner with respect to controls. No differences among groups were found regarding GFAP and Vim immunoreactivity and TUNEL positivity. Instead, pravastatin-treated animals presented a more marked cerebral eNOS immunoreactivity as compared with controls. In agreement with immunohistochemistry, immunoblot revealed dose-dependent increases in cerebral levels of eNOS in pravastatin rats. Our data confirm statin neuroprotection in cerebral ischemia. In particular, it is of great interest that a single i.v. Pravastatin administration reduced cerebral oedema by upregulating eNOS expression/activity. This, by increasing vascular NO bioavailability, could have produced proximal vasodilation and contributed to reducing perfusional deficit. It is worthy stressing how important the anti-oedema action is that pravastatin seems to exert. Indeed, cerebral oedema, when widespread and beyond limits of physiological compensation, causes endocranic hypertension and additional cerebral damage over time., (Copyright © 2011 Elsevier B.V. All rights reserved.) more...

Since mild thermal stress seems to exert neuroprotection via induction of heat-shock protein 70 kDa (hsp70), we tested whether hsp70 would preserve striatal bioelectrical activity under conditions of mitochondrial impairment. Corticostriatal slices from rats that had undergone mild thermal stress were exposed to either rotenone or 3-nitropropionic acid (3-NP), that selectively inhibits mitochondrial complex I and complex II, respectively. Rotenone is utilized to obtain an experimental model of Parkinson's disease while 3-NP replicates Huntington's disease phenotype in experimental animals. The cerebral hsp70 increase did not alter field potential amplitude of the slices but partially protected them against rotenone-induced neurotoxicity. Similarly, induction of hsp70 had also a partial neuroprotective effect on the neurotoxicity caused by 3-NP on striatal field potential. Since rotenone and 3-NP treatments mimic the mitochondrial impairment and oxidative stress that contribute to development of Parkinson's disease and Huntington's disease, these data suggest that induction of hsp70 might represent a possible neuroprotective mechanism against the pathophysiological chain of events implicated in these neurodegenerative disorders. more...

The basal ganglia circuit plays a key role in the regulation of voluntary movements as well as in behavioural control and cognitive functions. The main pathogenic role of mitochondrial dysfunctions is now accepted in the neurodegenerative process and the mitochondria have been successfully used as subcellular targets to obtain relevant experimental models of basal ganglia neurodegenerative disorders. Mitochondrial toxins act through an inhibition of the respiratory chain complexes. These toxins, by uncoupling cellular respiration, shift the cell into a state of oxidative stress and trigger several bidirectional links with the excitotoxic process. Moreover, the in vitro inhibition of the respiratory chain complexes alters the electrophysiological properties of the neurons. The downstream effects triggered by mitochondrial complexes inhibition provide a model integrating genetic and environmental pathogenic factors to explain the selective neuronal vulnerability. more...