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1.
Br J Pharmacol ; 150(5): 595-603, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17245369

ABSTRACT

BACKGROUND AND PURPOSE: In circulatory shock, melanocortins have life-saving effects likely to be mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in haemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists. EXPERIMENTAL APPROACH: Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non-selective agonist [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP--MSH) or with the selective MC4 agonists RO27-3225 and PG-931. Cardiovascular and respiratory functions were continuously monitored for 2 h; survival rate was recorded up to 24 h. Free radicals in blood were measured using electron spin resonance spectrometry; tissue damage was evaluated histologically 25 min or 24 h after treatment. KEY RESULTS: All shocked rats treated with saline died within 30-35 min. Treatment with NDP--MSH, RO27-3225 and PG-931 produced a dose-dependent (13-108 nmol kg-1 i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline-treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC4 receptor antagonist HS024. Moreover, treatment with RO27-3225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals. CONCLUSIONS AND IMPLICATIONS: Stimulation of MC4 receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC4 receptor agonists could have a protective role against multiple organ failure following circulatory shock.


Subject(s)
Multiple Organ Failure/prevention & control , Peptides, Cyclic/pharmacology , Receptor, Melanocortin, Type 4/agonists , Shock, Hemorrhagic/drug therapy , alpha-MSH/analogs & derivatives , Animals , Blood Pressure/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Free Radicals/blood , Heart Rate/drug effects , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Multiple Organ Failure/metabolism , Multiple Organ Failure/pathology , Multiple Organ Failure/physiopathology , Myocardium/pathology , Peptides, Cyclic/therapeutic use , Rats , Rats, Wistar , Receptor, Melanocortin, Type 4/metabolism , Respiratory Mechanics , Severity of Illness Index , Shock, Hemorrhagic/metabolism , Shock, Hemorrhagic/pathology , Shock, Hemorrhagic/physiopathology , Time Factors , alpha-MSH/pharmacology , alpha-MSH/therapeutic use
2.
J Neural Transm (Vienna) ; 112(1): 163-9, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15599614

ABSTRACT

Homocysteine (HC) may work inter alia as a Volume Transmission signal since HC is present in the brain and cerebrospinal fluid and binds to NMDA receptors. Furthermore, in cell cultures increased HC formation increases its export. In the present study we have shown that after intravenous injection in intact animals HC penetrates the blood-brain barrier. Hence, it works as a blood-born humoral signal. Furthermore, we have studied HC plasma levels in a group of Alzheimer's (AD) patients and compared with a group of age-matched patients. It has been confirmed that a positive correlation exists between age and HC plasma levels in the control group, but not in the AD patients. These results may depend on the fact that in AD patients high HC plasma levels (possibly associated with high glycine levels and/or excessive glutamate release) have favored neurodegeneration and, once this pathological process has been triggered off, the plasma HC levels become independent of the "physiological" aging-induced increase of HC plasma levels.


Subject(s)
Alzheimer Disease/blood , Homocysteine/blood , Nerve Degeneration/blood , Aged , Aged, 80 and over , Alzheimer Disease/physiopathology , Animals , Female , Humans , Male , Nerve Degeneration/physiopathology , Rats , Rats, Sprague-Dawley , Synaptic Transmission/physiology
3.
Neurotox Res ; 6(4): 327-32, 2004.
Article in English | MEDLINE | ID: mdl-15545016

ABSTRACT

Homocysteine (HC) and dehydroepiandrosterone sulphate (DHEAS) plasma levels have been evaluated in groups of male and female patients with Parkinson's disease (PD) and in a group of female patients with Alzheimer's disease (AD) and compared with the corresponding plasma levels observed in a group of age-matched subjects. It has been confirmed that HC plasma levels are enhanced in both PD and AD patients. As far as the DHEAS plasma levels are concerned no changes have been observed in PD patients while a marked decrease has been observed in AD patients. These results support the view that while the pro-oxidant effects of HC and its agonist action at NMDA receptors can play a role in both neurodegenerative diseases, the role of DHEAS is more complex and may be an important factor only in certain neurodegenerative diseases. Thus, according to the present study DHEAS is likely to be involved in AD but not in PD.


Subject(s)
Alzheimer Disease/blood , Dehydroepiandrosterone Sulfate/blood , Homocysteine/blood , Parkinson Disease/blood , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
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