Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We conducted the present study to investigate the effects of 5-hydroxytryptamine agonists on brain morphology after the induction of focal cerebral ischemia by permanent occlusion of the left middle cerebral artery in rats and mice. Forty-eight hours after vessel occlusion, the damage was quantified in rats by planimetry and subsequent integration on cresyl violet-stained serial sections and in mice by planimetric analysis of the damaged cortical surface after counterstaining with carbon black. All 5-HT1A agonists investigated substantially decreased cortical infarct size in the rat focal ischemia model (p less than 0.05). Drugs were applied 30 minutes before the induction of ischemia, and efficacy was demonstrated for 8-OH-DPAT (1 mg/kg s.c.), buspirone (10 mg/kg i.p.), gepirone (10 mg/kg i.p.), ipsapirone (10 or 30 mg/kg i.p.), and Bay R 1531 (1 mg/kg i.p.). The most pronounced effects were seen with the higher dose of ipsapirone and Bay R 1531, both compounds reducing cortical infarct size by more than 60%. Except for 8-OH-DPAT, the 5-HT1A agonists also caused a reduction in total infarct volumes. In a separate series, ipsapirone (30 mg/kg i.p.), applied 1 hour after vessel occlusion, led to a reduction in cortical and total infarct volumes by about 50% compared with corresponding controls (p less than 0.05). In neither series was striatal damage influenced. We tested the compounds in the mouse ischemia model over a broad dose range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-hydroxytryptamine1A agonists. A new therapeutic principle for stroke treatment. 214 35

The activation of 5-hydroxytryptamine receptors exerts an inhibitory influence on neuronal activity in a way similar to the activation gamma-amino-n-butyric acid and adenosine A1 receptors. Therefore, we hypothesized that 5-HT1A-receptor agonists might exert a neuroprotective effect. We tested the full agonists Bay R 1531 and 8-OH-DPAT and the partial agonists ipsapirone and gepirone in the model of transient global ischemia in the Mongolian gerbil. Ipsapirone protected 53% of pyramidal neurons (p less than 0.05) in the CA1 area of the hippocampus from ischemic damage at a dose of 3 mg/kg. Bay R 1531 showed a powerful neuroprotective effect with 100% preservation of neurons at a dose of 3 mg/kg (p less than 0.001) while gepirone and 8-OH-DPAT were ineffective. These findings suggest that 5-HT1A-receptor agonists might be effective tools for the therapy of cerebral ischemia. However, the varying results indicate that transient forebrain ischemia in the gerbil may not be the optimal model system to demonstrate clearly the neuroprotective activity of these compounds.
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PMID:Effects of 5-hydroxytryptamine1A-receptor agonists on hippocampal damage after transient forebrain ischemia in the Mongolian gerbil. 214 36

The effect of ischemia on the properties of 5-hydroxytryptamine1A + B (5-HT1A+B) and 5-hydroxytryptamine1B (5-HT1B) binding sites, physical-state "fluidity" of the membrane, and its susceptibility to peroxidation in vitro was investigated in the cerebral cortex of gerbils. Ischemia was induced by bilateral carotid artery occlusion for 15 min alone or with release for 1 h. Ischemia both with and without reflow decreased the number of 5-HT1A + B and 5-HT1B binding sites, whereas ischemia and reflow altered the affinity for 5-HT1B binding sites. Resistance to the temperature-dependent increase in "fluidity" of the membrane was detected (by fluorescence anisotropy using 1,6-diphenyl-1,3,5-hexatriene as a probe) after ischemia and reflow but not in ischemia alone. Susceptibility of the membranes to Fe2+- and ascorbic acid-stimulated lipid peroxidation in vitro was decreased following ischemia and recirculation only. These findings strongly suggest that the composition and the function of the membrane are markedly disturbed during recirculation after ischemia.
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PMID:Ischemic modification of cerebrocortical membranes: 5-hydroxytryptamine receptors, fluidity, and inducible in vitro lipid peroxidation. 274 37

We have examined the significance of the serotonergic system in the pathophysiology of ischemic brain damage. Permanent occlusion of the middle cerebral artery (MCA) was performed in male NMRI mice. After 48 h, the animals received a transcardiac injection of carbon black. The area of ischemia was restricted to the neocortex and its size was determined planimetrically by means of an image analyzing system. In control experiments, the NMDA antagonist dizocilpine (MK-801), the AMPA/kainate antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline) and the L-type calcium channel blocker nimodipine all produced a significant reduction in ischemic injury of the mouse neocortex. Interestingly, all of the 5-HT1A agonists tested (ipsapirone, CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine ] and urapidil) were equally efficacious in reducing ischemic injury. On the other hand, the 5-HT2 antagonist naftidrofuryl failed to protect the brain tissue significantly against ischemic brain damage. Roxindole, a 5-HT1A agonist and 5-HT uptake inhibitor, was the most potent serotonergic compound tested. In order to examine the effects of 5-HT1A receptor activation in a different context, 10 min of forebrain ischemia was induced in male Wistar rats by a bilateral occlusion of the common carotid arteries combined with systemic hypotension. Administration of the 5-HT1A agonist CM 57493 reduced the neuronal damage within the ventral hippocampus and the entorhinal cortex as assessed histologically 7 days after ischemia. Finally, we found that 5-HT1A agonists are capable of reducing neuronal damage of cultured neocortical and hippocampal neurons subjected to a chemical hypoxia or glutamate in a dose dependent manner. These data suggest that 5-HT, released during ischemia, may have protective effects in the pathophysiology of ischemic brain damage through a direct action on neurons mediated via the inhibitory 5-HT1A receptor subtype. The results obtained from different in vivo and in vitro models indicate that 5-HT1A agonists are promising agents for the treatment of ischemic brain disorders.
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PMID:Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role of serotonin in cerebral ischemia. 811 77

Apneusis is a disturbance of respiratory rhythm characterized by severely prolonged inspiratory effort. It may occur after damage to the respiratory network within the lower brain stem and pons from an overdose of central nervous system depressants, blockade of glutamate receptors, asphyxia, hypoxia, or ischemia. Experimental studies conducted on laboratory mammals, such as anesthetized cats and rats, suggest that apneusis results mostly from depression of glutamatergic synaptic processes that are necessary for activation of inhibitory mechanisms that terminate inspiration. The impairment of synaptic transmission leads to prolonged inspiratory efforts and apneustic discharges of brainstem respiratory neurons. Apneustic patterns can be consistently converted to normal by administration of serotonin type 1A (5-HT1A) receptor agonists. This observation encouraged a treatment of severe apneusis with buspirone, an agonist for 5-HT1A receptors, in a child after neurosurgery for an astrocytoma in the pons and medulla oblongata. Oral administration of buspirone produced a prompt and highly effective remission of apneusis without side effects. Treatment with 5-HT1A agonists, therefore, might offer a novel and effective pharmacotherapy against apneustic disturbances of breathing.
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PMID:Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist. 900 56

To clarify the serotonergic mechanisms involved in the protection against ischemic neuronal damage, ZD-211 (citalopram HBr), a serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitor, or buspirone, a 5-HT1A agonist, was locally administered into the hippocampus of gerbils. Additionally, to clarify the role of the 5-HT nervous system in the hippocampus during ischemic neuronal damage, animals were subjected to the local administration of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, before ischemia challenge. Gerbils received intrahippocampal administration of ZD-211 (200 nmol/animal) or buspirone (20 nmol/animal) before 5-min ischemia. 5,7-DHT was intrahippocampally administered 7 days before a 2-min non-lethal ischemia challenge. In vehicle-treated animals subjected to 5 min of ischemia, almost all hippocampal CA1 pyramidal neurons were lost. The treatment with ZD-211 or buspirone showed a significant protective effect, and the number of neurons was significantly increased compared to vehicle-treated animals. Pretreatment with NAN-190, a 5-HT1A antagonist, completely abolished the protective effect of ZD-211 or buspirone. In the 5,7-DHT-treated animals, the number of neurons was significantly reduced following 2 min of ischemia compared to vehicle-treated animals in which this period of ischemia is non-lethal. Thus, intrahippocampal treatment with ZD-211 or buspirone can protect neuronal damage following transient ischemia in gerbils. These effects of ZD-211 and buspirone were mediated through the 5-HT1A receptor in the hippocampus. Furthermore, the destruction of the 5-HT nervous system in the hippocampus aggravated ischemic neuronal damage. Therefore, this study showed that the enhanced activity of the 5-HT nervous system in the hippocampus may protect against neuronal damage following cerebral ischemia.
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PMID:Role of hippocampal serotonergic neurons in ischemic neuronal death. 906 88

It has been shown recently that Bay X 3702 ((-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1, 2,-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride), a highly potent and selective 5-HT1A receptor agonist, has a neuroprotective potency associated with its ability to inhibit ischemia-induced excessive release of glutamate. 5-HT1A receptors are highly expressed in brain areas, such as the hippocampus and the cerebral cortex, sensitive to neuronal damage induced by ischemic stroke or brain trauma. Therefore, we investigated whether Bay X 3702 can rescue cultured hippocampal neurons subjected to excitotoxic damage. The hippocampal neurons exposed to 0.5 mM L-glutamate for 1 h had pronounced damage characteristic of neuronal necrosis as evaluated 18 h later by trypan blue staining and morphological criteria. However, treatment with Bay X 3702 (0.001 to 1 microM) reduced the number of damaged neurons, and preserved cell morphology and integrity of the neuronal network. Bay X 3702 was added immediately after the end of exposure to glutamate and was present until the evaluation of neuronal damage. Furthermore, the neuroprotective activity of Bay X 3702 (0.1 microM) was abolished by WAY 100635 (N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl cyclo-hexanecarboxamide) (1 microM), a selective 5-HT1A receptor antagonist, indicating that the neurorescuing activity of Bay X 3702 was mediated via stimulation of 5-HT1A receptors. Additionally, we attempted to find whether the drug could protect rat brain tissue from ischemic insult due to permanent occlusion of the middle cerebral artery in rats. Bay X 3702 (12 and 40 microg/kg), infused within a period of 4 h, immediately after induction of ischemia greatly reduced cortical infarct volume (57 and 55% of controls, respectively) suggesting that this drug might be useful for the treatment of acute cerebral infarction.
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PMID:Neuroprotective effect of 5-HT1A receptor agonist, Bay X 3702, demonstrated in vitro and in vivo. 983 97

Different receptor subtypes mediate the effects produced by serotonin (5-HT) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia. In order to better define the pharmacological profile and determine the selectivity for the 5-HT receptor type, the properties of the new 5-HT1A receptor agonist 2[[4-(o-methoxyphenyl)piperazin-1-yl]-methyl]-1.3-dioxoperhydroimidazo[1.5-a]pyridine (B-20991), an arylpiperazine derivative, have now been further studied. B-20991 was found to antagonize the forskolin-induced increase of cAMP synthesis in a HeLa cell line transfected with the human 5-HT1A in a process sensitive to the selective blocker N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-dependent inhibition of the spontaneous on-going activity of serotonin (5-HT) neurons in the dorsal raphe nucleus in rats, an effect that was reversed by treatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT1A receptors. Additional activation of 5-HT1A postsynaptic receptors was indicated by the increase of corticosterone plasma levels induced by B-20991 in the rat. These results demonstrate that B-20991 is a selective 5-HT1A receptor agonist acting both pre- and postsynaptically, which represents an useful pharmacological tool to study 5-HT1A-receptor-mediated effects.
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PMID:Biochemical, electrophysiological and neurohormonal studies with B-20991, a selective 5-HT1A receptor agonist. 1136 1

Using positron emission tomography (PET) and microdialysis, the present study showed that neuronal damages after transient focal ischemia was partly induced by hyperactivation of the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system through modulations of dopamine D, and serotonin 5-HT1A receptors in the living brains of cynomolgus monkeys. Occlusion of the right middle cerebral artery for 3 hours suppressed CBF in the striatum, and reperfusion induced hyperperfusion in the neocortex and striatum of the occluded side. Six hours after reperfusion, the activity of the cAMP second messenger system assayed with [11C]rolipram was significantly facilitated in the neocortex and striatum where CBF was lowered more than 40% of normal during occlusion ("ischemic" area). Seven days later, impaired dopamine D1 and 5-HT1A receptor binding, measured with [11C]SCH23390 and [carbonyl-11C]WAY-100635, respectively, was observed in the ischemic area. Microdialysis analysis revealed that the striatal dopamine level provided a transient and marked increased during occlusion and after reperfusion, whereas the cortical serotonin level transiently increased only after reperfusion, and was at an undetectable level thereafter. Administration of rolipram (0.1 and 1 mg/kg, intravenously) during occlusion facilitated reduction of dopamine D1 binding, whereas rolipram administration 6 hours after reperfusion induced a further decrease in 5-HT1A receptor binding. These results suggest that the activation of cAMP second messenger system modulated by dopamine D1 and 5-HT1A receptors could be involved in the neuronal degeneration after transient cerebral ischemic insult.
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PMID:Transient focal ischemia affects the cAMP second messenger system and coupled dopamine D1 and 5-HT1A receptors in the living monkey brain: a positron emission tomography study using microdialysis. 1536 20

We assess the effects of ipsapirone (a 5-HT1A receptor agonist), ketanserin (a 5-HT2A receptor antagonist), (-)-pindolol (a 5-HT1A receptor antagonist), and DOI (a 5-HT2A receptor agonist) on heatstroke in a rat model. Animals, under urethane anesthesia, were exposed to high ambient temperature of 42 degrees C until mean arterial pressure and local cerebral blood flow in the striatum began to decrease, which was arbitrarily defined as the onset of heatstroke. Normothermic controls were exposed to room temperature of 24 degrees C. In rats treated with normal saline immediately before the initiation of heat stress, the values for survival time were found to be 21 to 25 min. Systemic administration of ipsapirone (10 mg/kg) or ketanserin (2 mg/kg) immediately before the initiation of heat stress significantly increased the survival time to new values of 92 to 104 min. Combined treatment with ipsapirone and ketanserin had additive effects (survival time of 156-194 min). In contrast, systemic administration of (-)-pindolol (2 mg/kg) or DOI (2 mg/kg) significantly decreased the survival time to new values of 2 to 3 min. In vehicle-treated heatstroke rats, the values for core temperature, intracranial pressure, and the extracellular levels of cellular ischemia (e.g., glutamate and lactate/pyruvate ratio) or damage (e.g., glycerol) markers and neuronal damage scores in striatum were significantly higher than those of normothermic controls. On the other hand, the values for mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of O2 were significantly lower than those of normothermic controls. The heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral hypoperfusion and hypoxia, and increased levels of cellular ischemia and damage markers in striatum were all significantly attenuated by prior administration of ipsapirone or ketanserin. The present results strongly suggest that previous activation of 5-HT1A receptors or antagonism of 5-HT2A receptors protects against heatstroke by reducing circulatory shock and cerebral ischemia, whereas prior antagonism of 5-HT1A receptors or activation of 5-HT2A receptors exacerbates heatstroke.
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PMID:Ipsapirone and ketanserin protects against circulatory shock, intracranial hypertension, and cerebral ischemia during heatstroke. 1620 18


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