Biomedical subjects

Marco Costanzi

Publications and source records attributed to Marco Costanzi.

4 recordsLinked to original sources

PubMed2006

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation.

The altered function and/or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDAR-mediated toxicity is postulated to play a pivotal role.

Alzheimer Disease↗

PubMed2004

Effects of anandamide and morphine combinations on memory consolidation in cd1 mice: involvement of dopaminergic mechanisms.

In the present research the interaction between the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) and morphine in memory consolidation was investigated. Four sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. The drugs were administered intraperitoneally after training of the animals in the apparatus. In the first set of experiments morphine (0.3 or 0.5, but not 0.15mg/kg) or anandamide (3 or 6 but not 1.5mg/kg) dose-dependently impaired memory consolidation. In the second set of experiments the administration of an otherwise ineffective dose of anandamide (1.5mg/kg) enhanced the memory impairment exerted by morphine (0.3 and 0.5mg/kg) when the drugs were injected immediately after training. In the third set of experiments the combined treatments of anandamide (1.5mg/kg) and morphine (0.5mg/kg) 2h after training were ineffective showing that the effects observed on performance following immediate posttraining administration of anandamide and morphine combinations were reflecting direct influences on memory consolidation. In the fourth set of experiments otherwise ineffective doses of the D1 DA receptor agonist SKF 38393 or the D2 DA receptor agonist LY 171555 antagonized the memory impairment produced by anandamide and morphine in combination, suggesting a possible involvement of dopaminergic mechanisms.

Animals↗

PubMed2003

Anandamide and memory in CD1 mice: effects of immobilization stress and of prior experience.

Five sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. In a first set, immediately posttraining administrations of the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) (3 or 6 mg/kg) dose-dependently impaired memory consolidation in mice. A lower dose (1.5 mg/kg) was ineffective. In a second set of experiments, which was carried out at the same time of the first set, preexposure of the animals to the testing apparatus decreased the effect of the drug, as compared with non-preexposed mice. In a third set of experiments, administration of anandamide (3 or 6 mg/kg) prior to the retention test did not affect the retention performance of mice given posttraining injections of either saline or anandamide. These findings indicate that the memory-impairing effects of posttraining administration of anandamide are not state-dependent. In the fourth and fifth series of experiments, carried out with non-preexposed mice, an otherwise ineffective immobilization stress (15 min) enhanced the memory-impairing effect of anandamide, and an otherwise ineffective dose of naltrexone (0.1 mg/kg) completely antagonized the effect. The results are discussed in terms of attenuation of emotionality, resulting in impaired retention, following anandamide administration, and of involvement of opioid system in the effect of this drug.

Animals↗

PubMed2003

Cannabinoids and memory: animal studies.

This review will consider studies concerning the effects of cannabinoid receptor agonists and antagonists on memory in laboratory animals. Two subtypes of cannabinoid receptors have been identified to date: the central CB1 subtype and the peripheral CB2 subtype. The receptor which specifically binds Delta9-tetrahydrocannabinol (Delta9-THC) and related compounds in rat and human brain has been discovered and cloned by a number of researchers. This cannabinoid receptor is localized with high concentrations in different brain areas, including hippocampus and amygdala, which play an important role in the modulation of memory. In recent years evidence has been obtained that cannabinoids influence memory processes. It has been shown, for example, that Delta9-THC impairs memory in rats, mice and monkeys tested in a variety of experimental conditions (radial maze, instrumental discrimination tasks, Morris water maze, etc.). In some of these researches the effect of Delta9-THC was antagonized by the CB1 receptor antagonist SR 141716A, showing the involvement of this subtype of cannabinoid receptor in its effect. Anandamide, arachidonylethanolamide, was recently discovered as the first endogenous ligand for the cannabinoid receptor. It has been reported to stimulate CB1 receptors and to mimic the pharmacological effects of cannabinoids. Experiments carried out by our group have shown that anandamide impairs memory consolidation in random bred mice (CD1), exerts genotype-dependent influences on memory in inbred strain of mice (C57 BL/6 and DBA/2), and that opioid and dopaminergic systems might be involved in its effects.

Animals↗