Adrenalectomy promotes a permanent decrease of plasma corticoid levels and a transient increase of apoptosis and the expression of Transforming Growth Factor β1 (TGF-β1) in hippocampus: effect of a TGF-β1 oligo-antisense

BACKGROUND: Corticosterone reduction produced by adrenalectomy (ADX) induces apoptosis in dentate gyrus (DG) of the hippocampus, an effect related to an increase in the expression of the pro-apoptotic gene bax. However it has been reported that there is also an increase of the anti-apoptotic gene bcl-2, suggesting the promotion of a neuroprotective phenomenon, perhaps related to the expression of transforming growth factor β1 (TGF-β1). Thus, we have investigated whether TGF-β1 levels are induced by ADX, and whether apoptosis is increased by blocking the expression of TGF-β1 with an antisense oligonucleotide (ASO) administered intracerebrally in corticosterone depleted rats. RESULTS: It was observed an increase of apoptosis in DG, 2 and 5 days after ADX, in agreement with a reduction of corticosterone levels. However, the effect of ADX on the number of apoptotic positive cells in DG was decreased 5 days after the lesion. In CA1–CA3 regions, the effect was only observed 2 days after ADX. TGF-β1 mRNA levels were increased 2 days after ADX. The sustained intracerebro-ventricular administration of a TGF-β1 ASO via an osmotic mini pump increased apoptosis levels in CA and DG regions 5 days after ADX as well as sham-operated control animals. No significant effect was observed following a scrambled-oligodeoxynucleotide treatment. CONCLUSION: The changes in both the pattern and the magnitude of apoptotic-cell morphology observed 2 and 5 days after ADX suggest that, as a consequence of the reduction of corticosteroids, some trophic mechanisms restricting cell death to a particular time window are elicited. Sustained intracerebral administration of TGF-β1 ASO increased the apoptosis promoted by ADX, suggesting that TGF-β1 plays an anti-apoptotic role in vivo in hippocampus

Contribution to van der Waerden's conjecture

AbstractIn this paper, we give two different elementary proofs for the inequality which states that the permanent of doubly stochastic matrices is greater than or equal to (n!/nn). This inequality was proved earlier by the author, and independently by Egorychev and Falikman

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Molecular modeling of salsolinol, a full Gi protein agonist of the μ-opioid receptor, within the receptor binding site

(R/S)-Salsolinol is a full agonist of the μ-opioid receptor (μOR) Gi protein pathway via its (S)-enantiomer and is functionally selective as it does not promote β-arrestin recruitment. Compared to (S)-salsolinol, the (R)-enantiomer is a less potent agonist of the Gi protein pathway. We have now studied the interactions of the salsolinol enantiomers docked in the binding pocket of the μOR to determine the molecular interactions that promote enantiomeric specificity and functional selectivity of (R/S)-salsolinol. Molecular dynamics simulations showed that (S)-salsolinol interacted with 8 of the 11 residues of the μOR binding site, enough to stabilize the molecule. (R)-Salsolinol showed higher mobility with fewer prevalent bonds. Hence, the methyl group bound to the (S)-stereogenic center promoted more favorable interactions in the μOR binding site than in the (R)-orientation. Because (S)-salsolinol is a small molecule (179.2 Da), it did not interact with residues implicated in the binding of larger morphinan agonists that are located toward the extracellular portion of the binding pocket: W3187.35, I3227.39, and Y3267.43. Our results suggest that contact with residues which (S)-salsolinol interacts with are enough to elicit Gi protein activation, and possibly define a minimum set required by μOR ligands to promote activation of the Gi protein pathway

Exploring neurocircuitries of the basal ganglia by intracerebral administration of selective neurotoxins

The detailed anatomy of the monoamine pathways of the rat, first described by the students of Nils-Åke Hillarp in Sweden, provided the basis for a neurocircuitry targeted pharmacology, leading to important therapeutic breakthroughs. Progress was achieved by the introduction of accurate lesion techniques based on selective neurotoxins. Systematic intracerebral injections of 6-hydroxydopamine let Urban Ungerstedt at the Karolinska Institutet, Stockholm, Sweden, to propose the first stereotaxic mapping of the monoamine pathways in the rat brain; and the 'Rotational Behaviour', as a classical model for screening drugs useful for alleviating Parkinson's disease and other neuropathologies. The direction of the rotational behaviour induced by drugs systematically administrated to unilaterally 6-hydroxydopamine-lesioned rats reveals their mechanism of action at dopamine synapses, as demonstrated when rotational behaviour was combined with microdialysis. The model was useful for proposing a ro

Birth asphyxia as the major complication in newborns: moving towards improved individual outcomes by prediction, targeted prevention and tailored medical care

Perinatal Asphyxia—oxygen deficit at delivery—can lead to severe hypoxic ischaemic organ damage in newborns followed by a fatal outcome or severe life-long pathologies. The severe insults often cause neurodegenerative diseases, mental retardation and epilepsies. The mild insults lead to so-called “minimal brain-damage disorders” such as attention deficits and hyperactivity, but can also be associated with the development of schizophrenia and life-long functional psychotic syndromes. Asphyxia followed by re-oxygenation can potentially lead to development of several neurodegenerative pathologies, diabetes type 2 and cancer. The task of individual prediction, targeted prevention and personalised treatments before a manifestation of the life-long chronic pathologies usually developed by newborns with asphyxic deficits, should be given the extraordinary priority in neonatology and paediatrics. Socio-economical impacts of educational measures and advanced strategies in development of robust diagnostic approaches targeted at effected molecular pathways, biomarker-candidates and potential drug-targets for tailored treatments are reviewed in the paper

Inhibition of DT-diaphorase is a requirement for Mn3+ to produce a 6-OH-dopamine like rotational behaviour

Intracerebral manganese administration together with the DT-diaphorase inhibitor dicoumarol (Mn3+ 40 nmol+-dicoumarol 2 nmol; in 4 μl) into the left medial forebrain bundle (MFB) produced a behavioural pattern characterised by contralateral behaviour when the rats were stimulated with apomorphine (0.5 mg/kg s.c.), in a manner similar to that when administered to unilaterally 6-hydroxy-dopamine-lesioned animals. The same animals rotated towards the opposite side (ipsilaterally) when stimulated with d-amphetamine (2 mg/kg s.c.). These results support the idea that DT-diaphorase plays a protective role in the dopaminergic systems