Biomedical subjects

Mario Herrera-Marschitz

Publications and source records attributed to Mario Herrera-Marschitz.

8 recordsLinked to original sources

PubMed2007

Nicotinamide prevents the effect of perinatal asphyxia on dopamine release evaluated with in vivo microdialysis 3 months after birth.

The present study shows that nicotinamide prevents the long-term effect of perinatal asphyxia on dopamine release monitored with in vivo microdialysis in the neostriatum of 3-month-old rats. Perinatal asphyxia was induced by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 16 or 20 min. Sibling, spontaneous, and caesarean-delivered pups were used as controls. Saline or nicotinamide (0.8 mmol/kg, i.p.) was administered to control and asphyxia-exposed animals 24, 48, and 72 h after birth. After weaning, the rats were randomly distributed in laboratory cages for animal care under standard ad libitum laboratory conditions. Approximately 3 months after birth, control and asphyxia-exposed animals were implanted with microdialysis probes into the lateral neostriatum for measuring extracellular monoamine and metabolite levels with HPLC-coupled to an electrochemical detection system under basal, D-amphetamine, and K(+)-depolarising conditions. There was an asphyxia-dependent decrease of extracellular dopamine levels, mainly observed during the periods when D-amphetamine (100 microM) or KCl (100 mM) was added into the perfusion medium. Compared to that observed in caesarean-delivered controls, the effect of D-amphetamine on dopamine levels was decreased by approximately 30 and 70% in animals exposed to 16 and 20 min of perinatal asphyxia, respectively. The effect of K(+)-depolarisation was decreased by 45 and 83% in animals exposed to the same periods of asphyxia, respectively. Both effects were prevented by nicotinamide, even if the treatment started 24 h after the insult. The present results support the idea of nicotinamide as an interesting molecule, useful for protecting against anoxia/ischemia occurring at neonatal stages. Nicotinamide can help to restore NADH/NAD+ depletion, but also to inhibit PARP-1 overactivation, a mechanism of action that has attracted attention, representing a novel target for neuroprotection following insults involving energy failure.

Amphetamine↗

PubMed2006

Adrenalectomy promotes a permanent decrease of plasma corticoid levels and a transient increase of apoptosis and the expression of Transforming Growth Factor beta1 (TGF-beta1) in hippocampus: effect of a TGF-beta1 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 beta1 (TGF-beta1). Thus, we have investigated whether TGF-beta1 levels are induced by ADX, and whether apoptosis is increased by blocking the expression of TGF-beta1 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-beta1 mRNA levels were increased 2 days after ADX. The sustained intracerebro-ventricular administration of a TGF-beta1 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-beta1 ASO increased the apoptosis promoted by ADX, suggesting that TGF-beta1 plays an anti-apoptotic role in vivo in hippocampus.

Adrenalectomy↗

PubMed2006

Neurochemical and behavioural characterisation of alkoxyamphetamine derivatives in rats.

The clinical utility of amphetamine and amphetamine analogues has been jeopardized by a number of side effects and toxicity, partly due to complex mechanisms of action. While some of the analogues have been individually characterised, there is still need for comparative studies, in particularly on their efficacy to release dopamine and 5-hydroxytryptamine, further enlightening some of the synaptic mechanisms conveying their actions. Thus, we have compared four alkoxyamphetamine derivatives, i.e., p-methoxyamphetamine; p-methoxymethamphetamine; methylenedioxyamphetamine, methylenedioxymethamphetamine, using methamphetamine, and D-amphetamine, as reference substances, on rotational behaviour and releasing mechanisms studied with in vivo microdialysis in rats. All alkoxylated-derivatives produced a long-lasting rotational behaviour at 10 mg/kg s.c., but the reference substances produced a strong rotation already at 2 mg/kg s.c. in 6-hydroxydopamine-lesioned rats. At the concentration of 100 micromolar, the alkoxylated-derivatives were equipotent to evoke dopamine and 5-hydroxytryptamine release in rat neostriatum, while D-amphetamine and methamphetamine were more efficient on dopamine release. Pre-treatment with methamphetamine or the alkoxylated-derivatives produced a remarkable decrease of the effect of K+ -depolarisation on both dopamine and 5-hydroxytryptamine release. The insertion of a methoxy or a methylenedioxy group on the benzene ring of D-amphetamine or methamphetamine, or N-methylation of the D-amphetamine molecule alters the selectivity of the compounds. The efficacy of the alkoxylated-derivatives on dopamine and 5-hydroxytryptamine release was similar, but stimulated less dopamine release and produced less rotational behaviour than D-amphetamine and methamphetamine. The lower efficacy of K+ -depolarisation following pre-treatments with the derivatives suggests an impairment of releasable monoamine stores. The present observations can enlighten the mechanisms of action of drugs showing a high risk for abuse among young populations.

Amphetamines↗

PubMed2004

Effect of perinatal asphyxia on tyrosine hydroxylase and D2 and D1 dopamine receptor mRNA levels expressed during early postnatal development in rat brain.

This study was designed to investigate the postnatal developmental plasticity of the mesostriatal and mesolimbic dopamine systems that occurs following perinatal asphyxia. The time course and patterning of the changes in levels of tyrosine hydroxylase (TH), and D1 and D2 dopamine receptor (R) mRNA in the cell body region, substantia nigra and ventral tegmental area (SN/VTA), and projection fields, striatum and limbic regions at the age of 6 and 24 h, and 1 week after asphyxia were studied with a quantitative reverse transcription polymerase chain reaction method with appropriate internal cRNA standard. In Caesarean-delivered control rats (Sprague-Dawley), TH, D2R and D1R mRNA levels showed regional and temporal specificity in both absolute levels and developmental kinetics during the first week of life. TH mRNA levels were >10-fold higher in SN/VTA than in striatum and limbic regions. Compared to Caesarean delivered controls, severe asphyxia (15-20 min) induced an increase of TH and D2R mRNA in SN/VTA 6 h and 1 week after birth. In addition, asphyxia induced an increase of TH mRNA in the projection fields, striatum and limbic regions, at 1 week. Perinatal asphyxia did not appear to exert any effect on D1R mRNA levels. No differences in any of the parameters were observed between spontaneous- and Caesarean-delivered animals. The present results indicate that perinatal asphyxia triggers coordinated changes in the expression of TH, and dopamine receptor mRNA in SN/VTA, striatum and limbic regions. These changes may affect differently dopamine D2R and D1R expression along development, contributing to long-term neurocircuitry imbalances.

Analysis of Variance↗

PubMed2004

Effects of the DT-diaphorase inhibitor dicumarol on striatal monoamine levels in L-DOPA and L-deprenyl pre-treated rats.

It has been proposed that DT-diaphorase plays a strategic role as a neuroprotective enzyme for monoamine neurons, perhaps together with monoamine oxidase (MAO). Thus, we investigated the long-term effects produced by DT-diaphorase inhibition with dicumarol injected unilaterally into the medial forebrain bundle (MFB) on monoamine and metabolite levels, alone, or following dopamine loading with 3,4-dihydroxyphenyl-L-alanine (L-DOPA) or MAO inhibition with L-deprenyl. Monoamine levels were assayed in aliquots from tissue samples from right and left striatum, including both dorsal and ventral regions. Dicumarol alone produced increases in 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), but not in dopamine and metabolite levels when assayed two weeks later. However, following preloading with L-DOPA (3 x 25 mg/kg s.c. 7, 4 and 1 h before surgery), a long-lasting bilateral increase in dopamine and metabolite levels was observed after dicumarol. No effect was observed on dopamine, 5-HT and metabolite levels after L-deprenyl (3 x 10 mg/kg, s.c.) alone, but the levels were unilaterally increased when L-deprenyl was followed by dicumarol. The same result was produced when both L-deprenyl and dicumarol were injected simultaneously into the same brain region. In conclusion, the present study shows that intracerebral inhibition of DT-diaphorase produces long-term changes in 5-HT, but also in dopamine metabolism when DT-diaphorase inhibition is combined with MAO inhibition by systemic or intracerebral treatment with L-deprenyl. It is suggested that both MAO and DT-diaphorase have to be inhibited for inducing long-term changes in monoamine metabolism. Thus, DT-diaphorase is an enzyme to be taken into account when L-DOPA is used to treat Parkinson's disease, or when an MAO-inhibitor is used to treat depression.

Animals↗

PubMed2002

Some aspects on the anatomy and function of central cholecystokinin systems.

The distribution of some cholecystokinin (CCK) systems in the rat brain is reviewed focusing on mesencephalic dopamine neurones which coexpress CCK and, in particular, on cortico-striatal CCK neurones which probably have glutamate as their co-transmitter. Functional studies based on the effect of several CCK(B) antagonists on phencyclidine-induced motility suggest that CCK is involved in locomotor behaviour causing inhibition in phencyclidine-treated habituated rats. In contrast, in unhabituated rats CCK stimulates exploratory behaviour. These effects may be related to the cortico-striatal CCK/glutamatergic pathway. Moreover, these studies provide evidence for endogenous release of a neuropeptide with behavioural consequences.

Animals↗

PubMed2002

Activation of extracellular signal-regulated kinases 1 and 2 by depolarization stimulates tyrosine hydroxylase phosphorylation and dopamine synthesis in rat brain.

Production of dopamine is regulated via phosphorylation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here we have used a preparation of rat striatal slices to examine the involvement of two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), in the depolarization-dependent regulation of TH phosphorylation and dopamine synthesis. Depolarization with elevated KCl (45 mm) caused an increase in the phosphorylation state and, thereby, activation of ERK1/2. The same stimulus also increased TH phosphorylation at Ser19, Ser31 and Ser40 (measured using site- and phospho-specific antibodies) and TH activity [measured as 3,4-dihydroxyphenylalanine (DOPA) accumulation]. A MAPK/ERK kinase inhibitor, PD098059, decreased the basal levels of phospho-ERK1/2 and prevented the increase in ERK1/2 phosphorylation induced by depolarization. PD098059 also decreased both basal and depolarization-induced phosphorylation of TH at Ser31 and reduced the increase in Ser40 phosphorylation induced by high potassium, but did not affect Ser19 phosphorylation. PD098059 alone inhibited basal TH activity and decreased the accumulation of DOPA induced by depolarization. These data provide evidence for the involvement of ERK1/2 in the regulation of the state of phosphorylation of TH at Ser31 and Ser40 and a correlation between ERK1/2-dependent phosphorylation of TH and stimulation of dopamine synthesis in the brain.

Action Potentials↗

PubMed2002

Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat.

The main purpose of this study was to characterize the initial neurotransmission cascade elicited by methamphetamine, analysing simultaneously with in vivo microdialysis monoamine, amino acid and neuropeptide release in substantia nigra and neostriatum of the rat. The main effect of a single systemic dose of methamphetamine (15 mg/kg, subcutaneously) was an increase in dopamine levels, both in substantia nigra ( approximately 10-fold) and neostriatum ( approximately 40-fold), accompanied by a significant, but lesser, increase in dynorphin B ( approximately two-fold, in both regions), and a decrease in monoamine metabolites. A similar effect was also observed after local administration of methamphetamine (100 microm) via the microdialysis probes, but restricted to the treated region. In other experiments, rats were repeatedly treated with methamphetamine or saline, with the last dose administered 12 h before microdialysis. Dopamine K+-stimulated release was decreased following repeated methamphetamine administration compared with that following saline, both in the substantia nigra (by approximately 65%) and neostriatum (by approximately 20%). In contrast, the effect of K+-depolarization on glutamate, aspartate and GABA levels was increased following repeated administration of methamphetamine. In conclusion, apart from an impairment of monoamine neurotransmission, repeated methamphetamine produces changes in amino acid homeostasis, probably leading to NMDA-receptor overstimulation.

Amino Acids↗