Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Adenosine is a depressant in the central nervous system with pre- and postsynaptic effects. In the present study, intracellular recording techniques were applied to investigate the modulatory effects of adenosine on projection neurons in the lateral rat amygdala (LA), maintained as slices in vitro. 2. Adenosine reversibly reduced the amplitude of a fast inhibitory postsynaptic potential (IPSP) that was evoked by electrical stimulation of the external capsule and pharmacologically isolated by applying an N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor antagonist, DL-(-)-2-amino-5-methyl-4-isoxazolepropionic acid and 6, 7-Dinitroquinoxaline-2,3-dione, respectively, and the gamma-aminobutyric acidB (GABAB) receptor antagonist CGP 35348. The postsynaptic potential that remained was abolished by locally applying bicuculline. 3. Adenosine reduced the amplitude of the fast IPSP on average by 40.3%. It had no significant effect on responses to exogenously applied GABA, on membrane potential or on input resistance, suggesting that the site of action was at presynaptic inhibitory interneurons in the LA. 4. The response to adenosine was mimicked by the selective adenosine A1 receptor agonist N6-cyclohexyladenosine and blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. 5. Neuronal responsiveness in the amygdala is largely controlled by inhibitory processes. Adenosine can presynaptically downregulate inhibitory postsynaptic responses and could exert dampening effects likely by depression of both excitatory and inhibitory neurotransmitter release.
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PMID:Modulatory effects of adenosine on inhibitory postsynaptic potentials in the lateral amygdala of the rat. 1049 51

Neuronal conductance was studied in anesthetized cats during cortically generated spike-wave seizures arising from slow sleep oscillation. Single and dual intracellular recordings from neocortical neurons were used. The changes were similar whether the seizures occurred spontaneously, or were evoked by electrical stimulation or induced by bicuculline. In all seizures, the conductance increased from the very onset of the seizure and returned to control values only at the end of the postictal depression. Simultaneous intracellular recordings from two neurons showed that the neuron leading the other neuron displayed the largest increase in membrane conductance. The changes in neuronal conductance during the two phases of the slow sleep oscillation, i.e. highest during depolarizations and lowest during hyperpolarizations, were similar to those occurring during the "spike" and "wave" components of seizures. (1) Maximal conductance was found during the paroxysmal depolarizing shift corresponding to the electroencephalogram "spike" (median: 252 nS; range: 90 to more than 400 nS). It was highest at the onset of the depolarized plateau and decreased thereafter. (2) During the hyperpolarization corresponding to the electroencephalogram "wave", the conductance was significantly lower (median: 71 nS; range: 41 to 140 nS). (3) The conductance was elevated during the fast runs (median: 230 nS; range: 92 to 350 nS) which occurred in two-thirds of the seizures. (4) The conductance values during postictal depression were situated between those measured during the seizure hyperpolarizations and during sleep hyperpolarizations. The conductance decreased exponentially back to the values of the slow sleep oscillation over the total duration of the postictal depression. The data suggest that the major mechanism underlying the "wave"-related hyperpolarizing component of spike-wave seizures relies mainly not on active inhibition, but on a mixture of disfacilitation and potassium currents.
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PMID:Changes in neuronal conductance during different components of cortically generated spike-wave seizures. 1071 28

Neuronal expression of brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of infarct tolerance (resistance to stroke) (H. Yanamoto et al., Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei, submitted to Brain Res.), a process that takes more than 7 days following a preconditioning of repetitive cortical spreading depression (CSD). To investigate whether an elevated level of BDNF protein in the brain solely protects neurons against temporary focal ischemia, recombinant (r)BDNF was infused into the rat neocortex. Recombinant BDNF (or vehicle: saline) was administered into the left neocortex via an implanted osmotic minipump for 2.5, 7, 10 or 14 days pre-ischemia, during ischemia and for 2 days post-ischemia (8 microgram in total) in male Sprague-Dawley rats (n=6 each). Temporary focal ischemia was induced in the left middle cerebral artery (MCA) territory by three-vessel occlusion of bilateral common carotid arteries (CCAs) and MCA for 2 h, and the cerebral infarct volume was analyzed 2 days after ischemia using TTC staining. Regional cerebral blood flow (rCBF) of the left neocortex was monitored after 14 days of intracerebral administration of BDNF or vehicle (n=10 each). The distribution of BDNF following different periods of rBDNF or vehicle-infusion was analyzed using immunohistochemical techniques (n=5 each). In the groups treated with 8 microgram of rhBDNF for 7, 10, or 14 days pre-ischemia, there were significant reductions of neocortical infarct volume compared to in the control or vehicle-treated groups (p<0.05). In the rCBF study, there was no significant change after the infusion of 8 microgram rhBDNF for 14 days. In the histological study, a wide distribution of BDNF-like immunoreactivity in the neuronal nuclei in the ipsilateral neocortex was demonstrated after the infusion of 8 microgram rhBDNF for 14 days. The BDNF-like immunoreactivity in the neuronal nuclei was enhanced at the time that the resistance to stroke was achieved by direct intra-cerebral infusion of exogenous rBDNF. Elucidating the function of the BDNF-like protein located in the neuronal nuclei should reveal a new strategy for neuroprotection against ischemic brain attack in humans.
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PMID:Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor. 1071 70

The paper discusses therapeutical approaches to Alzheimer's disease on the basis of pathological mechanisms responsible for neurodegeneration. Amyloid plaques called also senile plaques situated extracellularly cause loss of neurons, especially cholinergic neurons, that begin in Nucleus of Meynert. However, recent evidence from postmortem brain and fibroblast studies suggests that both adenylyl cyclase and phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruption may limit cholinergic pharmacotherapy. Other disorders, like disturbances in releasing Neuronal Growth Factor (NGF), oxidative stress, free Ca 2+, neuroimmunologic reactions are also important in AD brain changer. Only use of acetylcholine inhibitors: tacrine, donepezil and Gingko Biloba as well as nimodipine improved mental functions (MMSE screening). Neuroprotection of selegiline and NGF was observed. Behavioral symptoms often associated with dementia, like depression, anxiety, irritability, delusions, aggressiveness were treated with: olazepine, risperidone, haloperidol, clozapine, fluoxetine, paroxetine, sertraline, trazodon, dezypramine, lithium, benzodiazepines, carbamazepine and valproic acid. Drugs with strong anticholinergic effects, such as amitriptyline or imipramine should not be administered. Future studies on therapy to regulate metabolism of amyloid precursor-beta-APP are necessary to discover new efficient strategies.
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PMID:[Trials and perspectives in pharmacotherapy of Alzheimer's disease]. 1078 33

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.
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PMID:Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist. 1081 48

Neuronal nicotinic acetylcholine receptors (nAChRs) represent a large family of ligand-gated cation channels with diverse structures and properties. In contrast to the muscular nAChRs, the physiological functions of neuronal nAChRs are not well defined to date. Behavioral studies indicate that brain nAChRs participate in complex functions such as attention, memory, and cognition, whereas clinical data suggest their involvement in the pathogenesis of certain neuropsychiatric disorders (Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, etc.). For the majority of these disorders, the use of nAChRs' agonists may represent either a prophylactic (especially for Alzheimer's and Parkinson's diseases) or a symptomatic treatment. The possible mechanisms underlying these beneficial effects as well as the characteristics and potential therapeutic use of new, subtype-selective nAChRs agonists are presented.
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PMID:Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. 1088 Jul 17

Electroconvulsive therapy, which is used to treat refractory major depression in humans increases seizure threshold and decreases seizure duration. Moreover, the expression of brain derived neurotrophic factor induced by electroshocks (ECS) might protect hippocampal cells from death in patients suffering from depression. As temporal lobe epilepsy is linked to neuronal damage in the hippocampus, we tested the effect of repeated ECS on subsequent status epilepticus (SE) induced by lithium-pilocarpine and leading to cell death and temporal epilepsy in the rat. Eleven maximal ECS were applied via ear-clips to adult rats. The last one was applied 2 days before the induction of SE by lithium-pilocarpine. The rats were electroencephalographically recorded to study the SE characteristics. The rats treated with ECS before pilocarpine (ECS-pilo) developed partial limbic (score 2) and propagated seizures (score 5) with a longer latency than the rats that underwent SE alone (sham-pilo). Despite this delay in the initiation and propagation of the seizures, the same number of ECS- and sham-pilo rats developed SE with a similar characteristic pattern. The expression of c-Fos protein was down-regulated by repeated ECS in the amygdala and the cortex. In ECS-pilo rats, c-Fos expression was decreased in the piriform and entorhinal cortex and increased in the hilus of the dentate gyrus. Neuronal damage was identical in the forebrain areas of both groups, while it was worsened by ECS treatment in the substantia nigra pars reticulata, entorhinal and perirhinal cortices compared to sham-pilo rats. Finally, while 11 out of the 12 sham-pilo rats developed spontaneous recurrent seizures after a silent period of 40+/-27 days, only two out of the 10 ECS-pilo rats became epileptic, but after a prolonged latency of 106 and 151 days. One ECS-pilo rat developed electrographic infraclinical seizures and seven did not exhibit any seizures. Thus, the extensive neuronal damage occurring in the entorhinal and perirhinal cortices of the ECS-pilo rats seems to prevent the establishment of the hyperexcitable epileptic circuit.
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PMID:Electroshocks delay seizures and subsequent epileptogenesis but do not prevent neuronal damage in the lithium-pilocarpine model of epilepsy. 1099 2

Neuronal and glial isoforms of glutamate transporters show distinct distributions on membranes surrounding excitatory synapses, but specific roles for transporter subtypes remain unidentified. At parallel fiber (PF) synapses in cerebellum, neuronal glutamate transporters and metabotropic glutamate receptors (mGluRs) have overlapping postsynaptic distributions suggesting that postsynaptic transporters selectively regulate mGluR activation. We examined interactions between transporters and mGluRs by evoking mGluR-mediated excitatory postsynaptic currents (mGluR EPSCs) in slices of rat cerebellum. Selective inhibition of postsynaptic transporters enhanced mGluR EPSCs greater than 3-fold. Moreover, impairing glutamate uptake facilitated mGluR-dependent long-term depression at PF synapses. Our results demonstrate that uniquely positioned glutamate transporters strongly influence mGluR activation at cerebellar PF synapses. Postsynaptic glutamate uptake may serve as a general mechanism for regulating mGluR-initiated synaptic depression.
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PMID:Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. 1154 19

Neuronal tissues display high levels of protein kinase C (PKC) activity and isoform expression. The activation of this enzymatic system is important in the control of short and long term brain functions (ion channel regulation, receptor modulation, neurotransmitter release, synaptic potentiation/depression, neuronal survival) that are related to diverse brain pathologies. This review will describe recent developments in PKC regulation and changes in levels, isoforms and activation in acute and chronic neurodegenerative pathologies as well as in affective and psychic disorders. The recent availability of isoform selective inhibitors and activators may help to understand better the relevance of PKC in central nervous system (CNS) physiology and pathology and to identify new and safer pharmacologic strategies to be tested in different disease states.
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PMID:Protein kinase C isoforms as therapeutic targets in nervous system disease states. 1171 65

Neuronal potassium conductance has been shown to influence the sleep-wake cycle and REM sleep homeostasis. The periodic paralyses (PP) are characterized by episodes of muscular weakness associated with changes in serum potassium levels and, therefore, with possible alterations in extracellular neuronal potassium conductance. We submitted a sleep questionnaire to the members of Periodic Paralysis International Listserv, an on-line support and information group for subjects with PP. Three control groups were made up of patients with untreated depression, patients with depression under treatment and healthy subjects. Both subjects with PP and those with untreated depression had a higher frequency of self-reported insufficient sleep quality and a higher number of nocturnal awakenings than patients with depression under treatment and healthy controls. PP subjects had more self-reported daytime sleepiness, sleep-related hallucinations and nightmares/abnormal dreams than the other three groups. Patients affected by PP may have disrupted sleep architecture and homeostasis. In particular, we suggest that the stereotypical abnormal dreams reported by several patients may reflect oneiric elaboration of nocturnal episodes of flaccid paralysis, while the increased frequency of sleep-related hallucinations may be due to enhanced REM sleep expression associated with alterations of neuronal potassium conductance.
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PMID:Sleep complaints in periodic paralyses: a web survey. 1176 70


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