RESUMO
Introduction: Perinatal hypoxic-ischemic (HI) encephalopathy is defined as a neurological syndrome where the newborn suffers from acute ischemia and hypoxia during the perinatal period. New therapies are needed. The acylethanolamides, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), possess neuroprotective properties, and they could be effective against perinatal HI. These lipid mediators act through peroxisome proliferator-activated receptors subtype α (PPARα), or transient receptor potential vanilloid (TRPV), such as TRPV subtype 1 and 4. Materials and Methods: The objectives of this study were to discern: (1) the neuroprotective role of OEA and PEA in parietotemporal cortical neurons of newborn rats and mice subjected to hypoxia, and (2) the role of the receptors, PPARα, TRPV1, and TRPV4, in neuroprotective effects. Cell culture of cortical neurons and the lactate dehydrogenase assay was carried out. The role of receptors was discerned by using selective antagonist and agonist ligands, as well as knockout (KO) PPARα mice. Results: The findings indicate that OEA and PEA exert neuroprotective effects on cultured cortical neurons subjected to a hypoxic episode. These protective effects are not mediated by the receptors, PPARα, TRPV1, or TRPV4, because neither PPARα KO mice nor receptor ligands significantly modify OEA and PEA-induced effects. Blocking TRPV4 with RN1734 is neuroprotective per se, and cotreatment with OEA and PEA is able to enhance neuroprotective effects of the acylethanolamides. Since stimulating TRPV4 was devoid of effects on OEA and PEA-induced protective effects, effects of RN1734 cotreatment seem to be a consequence of additive actions. Conclusion: The lipid mediators, OEA and PEA, exert neuroprotective effects on cultured cortical neurons subjected to hypoxia. Coadministration of OEA or PEA, and the TRPV4 antagonist RN1734 is able to enhance neuroprotective effects. These in vitro results could be of utility for developing new therapeutic tools against perinatal HI.
RESUMO
RATIONALE: Repeated cocaine is known to induce morphological changes in dopaminergic circuits that are known to participate on cocaine-induced addictive changes. OBJECTIVE: The objective of the present study was to discern if acute or repeated regimens of daily cocaine (10 mg/kg) lead to reliable changes in the expression of some protein markers for neural plasticity such as synaptophysin, p21-Arc, alpha-tubulin (α-tubulin), and stathmin, in the mesolimbic dopaminergic circuit. Well-known changes in tyrosine hydroxylase and protein kinase A were used for confirming biochemical effects of repeated cocaine. Animals were subjected to three treatments: acute injection, 3-day injections, or sensitizing cocaine during 3 days followed by challenging doses at days 8 and 18. RESULTS: The findings revealed that sensitizing regimen of cocaine increases stathmin levels within the nucleus accumbens at day 18 of treatment, not day 8, without changes of synaptophysin, p21-Arc, or α-tubulin. This neural plasticity change seems not to be related to the development of motor sensitization. Other neural regions such as prefrontal cortex, dorsal striatum, and ventral tegmental area were not found to be affected. Repeated cocaine led to well-known short-term augmentation of tyrosine-hydroxylase and protein kinase A expressions in the nucleus accumbens, as well as maintained upregulation of tyrosine hydroxylase in the ventral tegmental area. CONCLUSIONS: As stathmin is an important regulatory protein of microtubule dynamics, this protein change would be linked to morphological changes after repeated cocaine. It was confirmed that upregulation of tyrosine hydroxylase within the ventral tegmental area may participate on the development of motor sensitization.