Preclinical and clinical studies with cysteamine and pantethine related to the central nervous system

1. 1. Cysteamine is formed by degradation of coenzyme A (CoA) and causes somatostatin (SS), prolactin and noradrenaline depletion in the brain and peripheral tissues. 2. 2. Cysteamine influences several behavioral processes, like active and passive avoidance behavior, open-field activity, kindled seizures, pain perception and SS-induced barrel rotation. 3. 3. Cysteamine has several established (cystinosis, radioprotection, acetaminophen poisoning) and theoretical (Huntington's disease, prolactinsecreting adenomas) indications in clinical practice. 4. 4. Pantethine is a naturally occurring compound which is metabolized to cysteamine. 5. 5. Pantethine depletes SS, prolactin and noradrenaline with lower efficacy compared to that of cysteamine. 6. 6. Pantethine is well tolerated by patients and has been suggested to treatment of atherosclerosis. The other possible clinical indications (alcoholism, Parkinson's disease, instead of cysteamine) are discussed

Neuropeptide Y (NPY) and the central nervous system: Distribution effects and possible relationship to neurological and psychiatric disorders

1. NPY is a 36 amino acid tyrosine-rich peptide. It is one of the most abundant and widely distributed neuropeptides known today within the central nervous system with particularly high concentrations in the hypothalamus and in several limbic regions. 2. NPY seems to coexist with other on neurotransmitters like somatostatin, galanin, GABA and the catecholamines noradrenaline and adrenaline in discrete brain regions. 3. NPY binding sites are widely distributed in the brain. However they do not always overlap with the distribution of NPY-like inanunoreactivity. 4. NPY is suggested to be involved in a large number of neuroendocrine functions, stress responses, circadian rhythms, central autonomic functions, eating and drinking behaviour, and sexual and motor behaviour. 5. Psychotropic drugs and neurotoxins can alter the NPY concentrations in discrete brain regions. 6. It is possible that NPY is related to various neurological and psychiatric illnesses, like Huntington's chorea, Alzheimer's disease, Parkinson's disease, eating disorders, and major depressive illness

Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients

CSF samples from ten healthy volunteers and 22 patients with major depression were collected by lumbar puncture at 9 a.m. and the content of monoamine metabolites, corticotropin releasing factor (CRF) and somatostatin (SRIF) was analyzed. Plasma concentrations of TSH following a TRH challenge test (200 gmg) and plasma cortisol following dexamethasone (1 mg; DST) were also analyzed. No relationships were observed between the CRF or SRIF concentrations and either basal or post-dexamethasone cortisol concentrations. Fourteen of 21 depressed patients were DST nonsuppressors using a plasma cortisol concentration cut off point ≧ 138 nmol/1. If a more conservative cut off point was used (> 290 nmol/1) seven out of 21 patients revealed a severity-related cortisol nonsuppression. No significant difference was observed between healthy volunteers and depressed patients with regard to TSH response to TRH. The CSF content of CRF was elevated and the content of SRIF reduced in the depressed patients. In the healthy volunteers an inverse relationship was observed between CSF concentrations of CRF and MHPG ( r= -0.72; P = 0.019); no relationship was observed between the concentrations of CRF and 5-HIAA or HVA. In the depressed patients positive correlations were found between CSF concentrations of CRF and 5-HIAA ( r = 0.59; P = 0.004) and between CRF and HVA ( r = 0.44; P = 0.042). These data are concordant with the view that norepinephrine and serotonin may be involved in the regulation of CRF secretion. However, these regulatory mechanisms may be altered in patients with major depression, where a normal noradrenergic inhibitory tone is postulated to be replaced by a serotoninergic stimulation of CRF release

Centrally administered neurotensin inhibits pentobarbital metabolism in mice but not in rats

Neurotensin (NT), a tridecapeptide with a widespread and uneven distribution within the central nervous system of mammals, is known to be involved in a variety of physiological, behavioral, endocrine and biochemical functions. Groups of rats and mice were given i.p. injections of pentobarbital followed by intracisternal administration of NT or saline. Following decapitation, the plasma, liver and brain concentrations of pentobarbital were measured with a gas chromatographic/mass fragmentographic method. In the mice, but not in the rats, the NT injection caused a substantial inhibition of the pentobarbital metabolism and a prolongation of the sleeping time. The mechanism(s) behind this inhibition still remains unclear

Possible relationship between neuropeptide Y (NPY) and major depression - evidence from human and animal studies

Neuropeptide Y (NPY) - like immunoreactivity - (LI) was measured in cerebrospinal fluid (CSF) from patients with major depressive disorder and from healthy volunteers without physical or mental illness. NPY-LI was significantly lower (p<0.001) in the CSF of depressives than in that of the healthy controls. Possible correlates to the findings in human CSF were studied in rats. Using the same assay for NPY-LI, the concentrations were measured in brain regions of rats following treatment with antidepressants (imipramine and zimeldine) or bulbectomy, a proposed animal model for depression. In the cerebral cortex, both antidepressants increased the Concentrations of NPY-LI, whereas bulbectomy had the opposite effect. The hypothalamic concentrations of the peptide were increased by imipramine only, whereas other brain regions were unaffected by either treatment. The effects of intracerebroventricular administration of NPY on open field and home cage behaviour were investigated in the rat. In the open field, NPY reduced activity in a dose-related manner. Behavioural adaptation or gross neurological functions were not influenced. NPY greatly suppressed home cage activity, an effect lasting throughout the recording period of 22 h. Thus, NPY abolished the normal circadian variation in activity and seemed to exert sedative effects when given centrally to rats

Effects of psychoactive drugs on delta sleep-inducing peptide concentrations in rat brain

The concentration of delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) in rat brain regions was determined by radioimmunoassay following treatment with various psychoactive drugs or adrenalectomy. The antidepressant drugs imipramine and zimeldine, given orally twice daily for three weeks, reduced the concentrations of DSIP-LI in the hypothalamus, frontal cortex and cerebellum. The effects of zimeldine were similar but somewhat less pronounced than those of imipramine. The neuroleptic drug haloperidol, given i.p. once daily for two weeks, increased the concentration of DSIP-LI in the hypothalamus, but not in the frontal cortex. A single dose of haloperidol did not affect the concentration of DSIP-LI in either region. Like haloperidol, pentobarbital elevated the concentration of DSIP-LI in the hypothalamus; however, this effect of the barbiturate was seen after single but not after repeated administration. Cortical concentrations of DSIP-LI were unaffected following both single and repeated pentobarbital administration. Finally, adrenalectomy increased the concentration of DSIP-LI in the hypothalamus, but not in the other brain regions. In conclusion, the DSIP concentration in rat brain regions may be altered by a variety of interventions. The most profound and general alterations were observed following administration of antidepressant drugs

Reduced CSF neurotensin concentration in drug-free schizophrenic patients

The concentration of the tridecapeptide neurotensin was measured in CSF from 76 drug-free schizophrenic patients and 45 healthy controls. A highly significant difference was found between the two groups with lower concentration of neurotensin-like immunoreactivity in schizophrenic patients. Normalization of the lower concentrations was obtained in the same patients during ongoing neuroleptic treatment. The neurotensin concentrations in CSF was unrelated to sex, age, duration of the disorder or to previous neuroleptic treatment. Neurotensin levels did not differ between patients with or without a family history. A significant correlation was found between low neurotensin concentrations and decreased motor activity. No significant relationship was seen between the increment in CSF concentrations of neurotensin and clinical improvement during neuroleptic treatment. No significant correlation between CSF concentrations of neurotensin and HVA or 5-HIAA, major metabolites of dopamine and serotonin, respectively, could be demonstrated. However, in a limited number of the schizophrenic patients in this population, a significant correlation was seen between neurotensin and the noradrenaline metabolite MOPEG. The data support the hypothesis that certain schizophrenic patients may have a compromised CNS neurotensin system which might increase vulnerability for this disorder