igmesine and Disease-Models--Animal

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.

Topics: Amnesia; Animals; Antidepressive Agents; Cinnamates; Cocaine-Related Disorders; Cyclopropanes; Disease Models, Animal; Drug Interactions; Humans; Hypericum; Ligands; Nootropic Agents; Piperazines; Plant Extracts; Psychopharmacology; Psychotic Disorders; Quinolones; Receptors, sigma; Steroids

So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

Topics: Animals; Anxiety; Cinnamates; Clinical Trials as Topic; Cyclopropanes; Depression; Diarrhea; Disease Models, Animal; Humans; Ligands; MEDLINE; Opipramol; Receptors, sigma

Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antidepressive Agents; Brain; Cinnamates; Conditioning, Psychological; Cyclopropanes; Dehydroepiandrosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fear; Injections, Intraventricular; Male; Peptide Fragments; Phenazocine; Pregnenolone; Progesterone; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Stress, Psychological

To assess the effects of the novel sigma receptor ligand JO 1784 ((+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride or igmesine hydrochloride) on behavioural and histological changes following cerebral ischaemia, the gerbil model of cerebral ischaemia was used. Two experiments were carried out. In the first animals were either sham operated, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bilateral carotid occlusion and histological evaluation carried out 96 h after surgery. In the second experiment the effects of JO 1784 administered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery on home cage activity and nitric oxide (NO) synthase activity in the cortex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided significant protection against this ischaemia-induced cell death (P < 0.03-0.005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0.0018-0.02). A large increase in NO synthase activity was observed in all brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Ischemia; Cell Count; Cinnamates; Citrulline; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Gerbillinae; Hippocampus; Male; Neuroprotective Agents; Time Factors