Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the etiology of Alzheimer's disease includes a wide range of dysfunction, the most essential dysfunction is probably in the mesolimbic acetylcholine (ACh) system. Three novel approaches to modulating ACh function were considered, somatostatin, serotonin (5-HT) and modulation of cortical ACh tone through angiotension II. Concerning somatostatin there is no correlation between the decrease in somatostatin binding sites in brain and choline-acetyl-transferase activity suggesting that modulating somatostatin is not a promising therapeutic approach to Alzheimer's disease. With 5-HT, evidence suggests that 5-HT receptors (in particular 5HT1A) are located on cholinergic projections and behavioral evidence suggests 5-HT modulation of memory function. This area could therefore develop rapidly, particularly in view of the recent discovery of numerous subtypes of 5-HT receptor. Concerning the third approach, recent evidence has shown that angiotensin converting enzyme (ACE) inhibitors can facilitate ACh release and also possess cognition enhancing activity. The possibility was also evoked that drugs such as piracetam might prevent age-related decreases in ACh receptor density. Concerning trophic factors (e.g. glutamate-induced neuronal sprouting) most approaches have induced amnesia but the search for partial glutamate agonists may have potential. Finally, a neuronal transplant approach was considered but was thought to be very difficult in view of the global brain shrinkage associated with aging and Alzheimer's disease.
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PMID:Biochemical models for cognition enhancers. 218 20

In the present study the effects of somatostatin and its analogs on active avoidance behavior, electroconvulsive shock (ECS)-induced retrograde amnesia, and spatial-discrimination learning were compared in rats. (D-Trp8, D-Cys14)-somatostatin (as did the somatostatin molecule itself) delayed the extinction of active avoidance behavior, antagonized ECS-induced amnesia, and did not modify spatial-discrimination learning. Des-Asn5-(D-Trp8, D-Ser13) somatostatin and des-AA1,2,4,5,12,13,-(D-Trp8) somatostatin did not influence these behaviors. The data suggest that certain parts of the somatostatin molecule are important for its behavioral actions.
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PMID:Somatostatin and (D-Trp8, D-Cys14)-somatostatin delay extinction and reverse electroconvulsive shock induced amnesia in rats. 287 76

The effects of a wide range of doses of systemically administered cysteamine were studied on locomotor behavior, passive avoidance memory, cortical and cerebrospinal fluid somatostatin-like immunoactivity and cortical levels of dopamine and norepinephrine. High doses of cysteamine (200 and 250 mg/kg s.c.) led to sustained locomotor activation. Doses of 150 mg/kg and above resulted in head and neck tremor and increased defecation. When cysteamine was administered immediately following the acquisition of a passive avoidance response, doses of 50 mg/kg and above resulted in significant attenuation of passive avoidance retention test performance. Cysteamine in doses of 50 mg/kg and above depleted cortical somatostatin-like immunoactivity by approximately 50%. The depletion of cortical somatostatin-like immunoactivity was accompanied by a rapid rise in somatostatin-like immunoactivity in cerebrospinal fluid. In addition to the depletion of somatostatin-like immunoactivity, high doses of cysteamine (150 mg/kg and above) produced changes in cortical levels of norepinephrine and dopamine, reminiscent of dopamine-beta-hydroxylase inhibition. The results of this series of experiments suggest that somatostatin, in addition to its effects on hormonal regulation, may play an important role in behavior and passive avoidance learning and memory. It is possible that the amnesia produced by cysteamine may have been due to the release of somatostatin into CSF from tissue stores, rather than somatostatin depletion per se. It is also possible that the catecholaminergic effects of high doses of cysteamine contribute to the behavioral deficits observed.
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PMID:Cysteamine-induced depletion of central somatostatin-like immunoactivity: effects on behavior, learning, memory and brain neurochemistry. 382 20

In the present study the role of beta-receptors in the behavioral action of somatostatin was investigated. Somatostatin inhibited extinction of the active avoidance behavior. Propranolol alone had no action on this behavior but significantly inhibited the peptide-induced effect. In the open-field test somatostatin induced locomotor activation; propranolol did not influence this effect of the peptide. Somatostatin inhibited electroconvulsive shock-induced amnesia. Propranolol alone had no action in this test, but significantly decreased the antiamnesic effect of the peptide. These results suggest that the central beta-receptors play an important role in the behavioral action of somatostatin.
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PMID:The effects of interaction between propranolol and somatostatin on the active avoidance behavior, open-field activity and electroconvulsive shock-induced amnesia of rats. 613 74

In the present study the effects of intracerebroventricularly [icv] administered somatostatin [linear and cyclic], somatostatin3-6, somatostatin7-10 and des AA1,2,4,5,12,13 [D-Trp8] somatostatin [ODT8-SS] were investigated on electroconvulsive shock [ECS]-induced retrograde amnesia in rats. The ECS significantly decreased the foot shock-induced avoidance latency, and thus caused retrograde amnesia. Somatostatin [linear and cyclic] in a dose of 0.6 nM had no action on the ECS-induced retrograde amnesia, while in doses of 3 nM and [cyclic only] 6 nM it significantly prevented it. Somatostatin3-6, somatostatin7-10 and ODT8-SS in doses of 0.6, 3 and 6 nM had no effect on the ECS-induced amnesia. These results indicate that the whole sequence of the original somatostatin molecule is needed to block the ECS-caused retrograde amnesia.
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PMID:The effects of somatostatin, its fragments and an analog on electroconvulsive shock-induced amnesia in rats. 614 72

The effects of pretreatment with atropine, haloperidol and phenoxybenzamine on somatostatin-induced antiamnesia were investigated. Somatostatin itself blocked electroconvulsive shock (ECS)-induced amnesia. The receptor blockers per se had no influence on the ECS-induced avoidance latency. Atropine and haloperidol did not inhibit somatostatin-induced antiamnesia, whereas phenoxybenzamine blocked it completely. The results suggest that the central noradrenergic system plays an important role in the mediation of the antiamnesic action of somatostatin.
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PMID:Phenoxybenzamine antagonizes somatostatin-induced antiamnesia in rats. 614 3

Starting from the hypothesis that drugs which specifically activate the hippocampal cholinergic nerve activity may ameliorate memory impairments, we carried out a series of evaluations for a novel cognitive enhancer using enhancement of penile erection as a sign of cholinergic activation, and found FR64822. The compound facilitated penile erection in naive rats, and it ameliorated scopolamine-induced amnesia of rats in passive avoidance tasks with bell-shaped dose-response curves, while it dose-dependently reduced body weight gain in Zucker fatty rats. Pretreatment with sulpiride (32 mg/kg, p.o.) hardly affected the former two activities, but significantly reduced the anorectic activity in Zucker rats. Further evaluation of FR64822 derivatives characterized a second compound, FR121196, which induces penile erection and memory enhancement, but not body weight reduction. Memory enhancing and erection stimulating activities of FR121196 were abolished in rats treated with either cysteamine (200 mg/kg, s.c.), a somatostatin depletor, or lesioning of the serotonergic raphe nuclei. Thus, classic whole animal studies based on a hypothesis proved to be efficient for reaching our objective, the discovery of a new drug. They also gave us insight into the common somatostatinergic and serotonergic mechanisms underlying penile erection and memory improvement.
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PMID:A screening concept based on a hypothesis led to the development of a putative cognitive enhancer that stimulates penile erection. 802 16

Our previous studies demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various rodent models of amnesia, through activation of the somatostatin neuronal system. To extend the antiamnesic action of FK960 to nonhuman primates, FK960 was evaluated for its ability to reverse the deficits in visual recognition memory produced by muscarinic cholinergic receptor blockade by scopolamine or N-methyl-D-aspartate receptor blockade by dizocilpine (MK-801) in four rhesus monkeys performing a computer-automated version of delayed nonmatching to sample, with a list length of 20 trial-unique graphic symbols. Furthermore, the effects of FK960 were compared with those of physostigmine, a cholinesterase inhibitor. Doses of FK960 (1, 3.2, 10, 32,100, 320 or 1000 microg/kg) injected i.m. 30 min before testing minimally affected visual recognition memory when administered alone. FK960 (1, 3.2, 10 or 32 microg/kg) significantly antagonized the deficits in visual recognition memory produced by scopolamine (10 microg/kg); the same doses of the drug minimally affected the deficits produced by dizocilpine (32 microg/kg). Similarly, physostigmine (3.2, 10 or 32 microg/kg) significantly and dose-dependently restored the visual recognition memory deficits produced by scopolamine (10 microg/kg) but not those produced by dizocilpine (32 microg/kg). From these results, we conclude that FK960 improves deficits in recognition memory associated with central cholinergic hypofunction in nonhuman primates, and we suggest that the therapeutic potential of this drug for patients with dementia should be evaluated.
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PMID:FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine. 906 4

Our previous studies have demonstrated that FK960 (FR59960; N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate), a novel antidementia piperazine derivative, exerts beneficial effects on memory deficits in various animal models of amnesia in rats [M. Yamazaki, N. Matsuoka, N. Maeda, Y. Ohkubo, I. Yamaguchi, FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the memory deficits in rats through a novel mechanism of action, J. Pharmacol. Exp. Ther., 279 (1996) 1157-1173.] and in rhesus monkeys [N. Matsuoka, T.G. Aigner, FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine, J. Pharmacol. Exp. Ther., 280 (1997) 1201-1209]. To clarify the synaptic mechanisms of its antiamnesic action, FK960 was investigated for its effects on the development of long-term potentiation (LTP) in guinea-pig hippocampal slices. The magnitude of LTP of population spike recorded in CA3 pyramidal neurons was significantly augmented by perfusing FK960 (10-9-10-6 M) for 25 min before and during tetanic stimulation of the mossy fibers, whereas the basal amplitude of population spikes before tetanus was hardly affected by the drug. The dose-response curve was bell-shaped with a maximal augmentation at 10-7 M. Scopolamine (10-6 M) per se had little effect on the magnitude of LTP in the mossy fiber-CA3 pathway, but significantly attenuated its enhancement by FK960 (10-7 M). In hippocampal slices from animals treated with cysteamine (200 mg/kg, s.c.), which was shown to deplete the hippocampal somatostatin, FK960 (10-7 M) hardly affected the LTP. These results suggest that FK960 enhances the magnitude of LTP in the mossy fiber-CA3 pathway through an activation of the cholinergic-somatostatinergic link in the hippocampal formation. Furthermore, it can be postulated that the drug regulates the cognitive function by modulating directly synaptic plasticity in the hippocampal neuronal network.
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PMID:FK960, a novel potential anti-dementia drug, augments long-term potentiation in mossy fiber-CA3 pathway of guinea-pig hippocampal slices. 962 44

In rats, on the 25th day after the start of a thiamine-deficient (TD) diet, impairment of avoidance learning was significantly induced in proportion to the decrease somatostatin (SST) fluorescence intensity in the cortex, amygdala, thalamus, hypothalamus, and hippocampus, including the CA1, CA2, and dentate gyrus (DG). Only a single injection of thiamine HCl (0.5 mg/rat, subcutaneous) on the 14th day after the start of a TD diet improved the amnesia to the level of the pair-fed control and prevented the decrease in the SST level. Whereas these reversal effects of thiamine treatment were not found when the treatment was given on the 21st day after the start of a TD diet. These results indicate that, after a certain degree of thiamine deficiency, TD-induced behavioral effects might be reversible, but some neuronal fibers might be irreversibly damaged, probably due to the reduction of thiamine-dependent enzymes in brain mitochondria. The results also suggest the possibility that SST in the brain may be closely related to the avoidance learning impairment induced by TD.
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PMID:Immunohistochemical estimation of rat brain somatostatin on avoidance learning impairment induced by thiamine deficiency. 1065 80


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