David Moranta

Chronic melatonin treatment and its precursor L-tryptophan improve the monoaminergic neurotransmission and related behavior in the aged rat brain

Abstract:  Melatonin has an important role in the aging process as a potential drug to relieve oxidative damage, a likely cause of age‐associated brain dysfunction. As age advances, the nocturnal production of melatonin decreases potentially causing physiological alterations. The present experiments were performed to study in vivo the effects of exogenously administered melatonin chronically on monoaminergic central neurotransmitters serotonin (5‐HT), dopamine (DA) and norepinephrine (NE) and behavioral tests in old rats. The accumulation of 5‐hydroxy‐tryptophan (5‐HTP) and L‐3,4‐dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in rat brain. Also neurotransmitters 5‐HT, DA and NE and some metabolites were quantified by HPLC. In control rats, an age‐related decline was observed in neurochemical parameters. However, chronic administration of melatonin (1 mg/kg/day, diluted in drinking water, 4 wk) significantly reversed the age‐induced deficits in all the monoaminergic neurotransmitters studied. Also, neurochemical parameters were analyzed after administration of melatonin biosynthesis precursor L‐tryptophan (240 mg/kg/day, i.p., at night for 4 wk) revealing similar improvement effects to those induced by melatonin. Behavioral data corresponded well with the neurochemical findings since spatial memory test in radial‐maze and motor coordination in rota‐rod were significantly improved after chronic melatonin treatment. In conclusion, these in vivo findings suggest that melatonin and L‐tryptophan treatments exert a long‐term effect on the 5‐HT, DA and NE neurotransmission by enhancing monoamine synthesis in aged rats, which might improve the age‐dependent deficits in cognition and motor coordination.

Acute, chronic and withdrawal effects of the cannabinoid receptor agonist WIN55212-2 on the sequential activation of MAPK/Raf-MEK-ERK signaling in the rat cerebral frontal cortex: short-term regulation by intrinsic and extrinsic pathways.

The cannabinoids (CB) modulate the extracellular signal‐regulated kinase (ERK), leading to various forms of plasticity in the brain. Little is known, however, on the in vivo short‐ and long‐term activation and regulation of the components of mitogen‐activated protein kinase (MAPK)/ERK signaling by CB. The CB agonist WIN55212‐2 (8 mg/kg) increased the immunodensities of phosphorylated c‐Raf‐1 (42%), MEK1/2 (63%), ERK1 (24%), and ERK2 (28%) in the rat cerebral frontal cortex. These effects were antagonized by SR141716A (rimonabant, 10 mg/kg), a selective CB1 receptor antagonist. Repeated WIN55212‐2 treatment (2–8 mg/kg for 5 days) resulted in tachyphylaxis to the acute activation of Raf‐MEK‐ERK signaling. Acute WIN55212‐2 also induced a hypothermic effect in rats, which was reduced after repeated administration (tolerance). Treatment with SR141716A after chronic WIN55212‐2 resulted in the expected cannabinoid withdrawal syndrome, without concomitant alterations in the phosphorylation state of c‐Raf‐1, MEK1/2, or ERK1/2. Pretreatment with SL327 (20 mg/kg, a MEK1/2 inhibitor) increased the basal phosphorylation of c‐Raf‐1 (40%) and MEK1/2 (74%; feedback regulation) and fully prevented the up‐regulation of ERK1/2 (23–31%) induced by WIN55212‐2. Pretreatment with MK801 (1 mg/kg, a NMDA receptor antagonist) effectively blocked the up‐regulation c‐Raf‐1 (41%), MEK1/2 (57%) and ERK1/2 (25–30%) induced by the CB agonist. The main findings demonstrate that the acute stimulation of CB1 receptors in the frontal cortex results in the sequential phosphorylation of Raf‐MEK‐ERK cascade, in which c‐Raf‐1 activation (rate‐limiting process) plays a crucial role. Moreover, the in vivo stimulating effect of WIN55212‐2 on Raf‐MEK‐ERK signaling is under the extrinsic regulation of an excitatory glutamatergic mechanism.

Ethanol desensitizes cannabinoid CB1 receptors modulating monoamine synthesis in the rat brain in vivo.

The endocannabinoid system and the cannabinoid CB(1) receptors are involved in the development of ethanol tolerance and dependence. This study aimed to investigate the in vivo sensitivity of a CB(1) receptor agonist (WIN 55,212-2) modulating the synthesis of 3,4-dihydroxy-phenylalanine/dopamine/noradrenaline (DOPA/DA/NA) and that of 5-hydroxy-tryptophan/serotonin (5-HTP/5-HT) in rat brain after ethanol treatment and withdrawal. In control rats, WIN 55,212-2 (4 mg/kg, i.p., for 1h), through a mechanism sensible to the CB(1) antagonist SR 141716A, increased the synthesis of DOPA/NA in a slice of brainstem containing the locus ceruleus (250%) and in the hippocampus (64%), and it reduced DOPA/DA synthesis in the striatum (47%). WIN 55,212-2 also decreased the synthesis of 5-HTP/5-HT in the locus ceruleus (43%), hippocampus (35%) and striatum (35%). In the locus ceruleus of ethanol-treated rats, the stimulatory effect of WIN 55,212-2 on DOPA/NA synthesis was abolished (acute treatment) or markedly attenuated (53-55%, chronic treatment and withdrawal), whereas in the hippocampus this effect was reduced only in chronic ethanol-withdrawn rats (33%). In the striatum of ethanol-treated rats (acute, chronic and withdrawal), the inhibitory effect of WIN 55,212-2 on DOPA/DA synthesis was completely blunted or markedly reduced. Similarly, the inhibitory effect of WIN 55,212-2 on 5-HTP/5-HT synthesis was reduced or abolished in the three brain regions after chronic ethanol and during withdrawal. These results indicate that treatment with ethanol in rats induces a functional desensitization of CB(1) receptors modulating the synthesis of brain monoamines.

Withdrawal from chronic ethanol increases the sensitivity of presynaptic 5-HT1A receptors modulating serotonin and dopamine synthesis in rat brain in vivo

The in vivo sensitivity of presynaptic 5-HT(1A) receptors (autoreceptors and heteroreceptors) modulating the synthesis of 5-hydroxytryptophan/serotonin (5-HTP/5-HT) and 3,4-dihydroxyphenylalanine/dopamine (DOPA/DA) in rat brain was investigated after ethanol treatment and withdrawal. In saline-treated rats as well as in acute ethanol (2 g/kg, intraperitoneally (i.p.), 2 h)- and chronic ethanol (2 g/kg for 7 days)-treated rats, a low dose of the 5-HT(1A) receptor agonist 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT; 0.1 mg/kg, i.p., 1 h) did not decrease the synthesis of 5-HTP in brain (except modestly in striatum; 20% after the chronic treatment) or that of DOPA in striatum. In contrast, in chronic ethanol-withdrawn rats (24 h), 8-OH-DPAT significantly decreased the synthesis of 5-HTP in the hippocampus (29%), cerebral cortex (41%) and striatum (33%) and that of DOPA in the striatum (28%). Similar effects were induced by the mixed 5-HT(1A) agonist/D(2) antagonist buspirone (1 mg/kg, i.p., 1 h) which also decreased 5-HTP synthesis in the hippocampus (24%), cerebral cortex (36%) and striatum (35%) of chronic ethanol-withdrawn rats. These results indicate that chronic ethanol and more clearly the spontaneous withdrawal from chronic ethanol induce supersensitivity of 5-HT(1A)-auto/heteroreceptors modulating the synthesis of 5-HT and DA in rat brain.

Improving effects of long-term growth hormone treatment on monoaminergic neurotransmission and related behavioral tests in aged rats.

An age-related decline in cognitive functions and physical performance has been associated with reductions in growth hormone (GH) secretion and brain neurotransmitter function. In vivo experiments were performed to study the long-term effects of exogenously administered GH on the central monoaminergic neurotransmitters serotonin, dopamine, and noradrenaline and behavioral tests in old Wistar rats. The accumulation of 5-hydroxytryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Also, the content of the neurotransmitters serotonin, dopamine, and noradrenaline and some metabolites was measured by high-pressure liquid chromatography (HPLC) in the hippocampus and striatum, brain regions involved in adult memory processing and motor coordination. The age-related decline observed in all the neurochemical parameters in control rats was significantly reversed after repeated subcutaneous administration of GH (2 mg/kg per day, 4 weeks). Thus, GH treatment exerted a long-term effect on serotonin, dopamine, and noradrenaline neurotransmission by enhancing neurotransmitter synthesis and metabolism in aged rats. The results obtained after examining working memory tasks in the eight-radial maze and motor ability in the Rotarod treadmill in aged rats were consistent with these neurochemical data; both tests were significantly improved after chronic GH treatment. Overall, these in vivo findings suggest that the positive effects induced by GH on serotonin, dopamine, and noradrenaline neurotransmitters might explain, at least in part, the effects of chronic GH treatment in improving cognitive and motor ability in aged rats, and could aid in preventing or delaying deficits in monoamines associated with learning or motor disabilities.

Effects of Resveratrol and Other Polyphenols on the Most Common Brain Age-Related Diseases

BACKGROUND With global increase in elderly population, modern societies must find strategies to reduce the consequences of aging process; thereby decreasing the incidence of age-related neurodegenerative diseases. Oxidative stress and recently inflammation, have been pointed out as the leading causes of brain aging. Thereby, the consumption or administration of antioxidant and anti-inflammatory molecules, such as polyphenols, is a beneficial strategy recommended for preventing brain aging and several brain age-related diseases. METHODS AND RESULTS Several studies suggest that long term consumption of dietary polyphenols offers protection against development of neurodegenerative diseases. These beneficial effects are in part due to their antioxidant and anti-inflammatory properties, together with their positive role in the modulation of processes involved in the physiopathology of several neurodegenerative diseases (e.g., epigenetic factors, amyloid deposition, cholinesterase inhibition, autophagy, and neurotrophic factors, among others). Altogether, these molecules open the door to the research of new neuroprotective strategies. This review summarizes the latest discoveries in how polyphenols can exert positive effects on brain health in aging, emphasizing those effects on the diseases that most commonly affect the brain during aging: Parkinsons Disease (PD), Alzheimers disease (AD), dementia and depression. Moreover, within are addressed the epigenetic effects of polyphenols as possible mediators in their positive effects on brain health, and the future challenges of research in this topic Conclusion: In brief, this review presents a report of state-of the art knowledge regarding the positive influences of polyphenols on the most common brain age-related diseases as well as in healthy brain aging.