Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serotonergic nervous system plays crucial roles in regulating psycho-emotional, cognitive, sensori-motor and autonomic functions. It is now known that multiple serotonin (5-hydroxytryptamine; 5-HT) receptors regulate extrapyramidal motor functions, which are implicated in pathogenesis and/or treatment of various neurological disorders (e.g., Parkinson's disease and drug-induced extrapyramidal motor deficits). Specifically, antagonism of 5-HT2A/2C receptors alleviates antipsychotic-induced extrapyramidal side effects (EPS) by relieving the 5-HT2A/2C receptor-mediated inhibition of nigral dopaminergic neuron activity and striatal dopamine release. Indeed, many of the second generation antipsychotics (e.g., risperidone, perospirone and olanzapine) commonly possess potent 5-HT2A/2C blocking actions which contribute to their atypical antipsychotic property. In addition, activation of 5-HT1A receptors also improves antipsychotic-induced EPS and motor disabilities in animal models of Parkinson's disease. Microinjection studies revealed that stimulation of postsynaptic 5-HT1A receptors in the striatum or motor cortex plays an important role in the antiparkinsonian actions. Furthermore, recent studies demonstrated that antagonism of 5-HT3 and 5-HT6 receptors alleviates extrapyramidal motor disorders while 5-HT4, 5-HT5, and 5-HT7 receptors are mostly inactive. These results encourage drug discovery research into new 5-HT receptor ligands that could improve current therapies for extrapyramidal motor disorders.
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PMID:Pathophysiological roles of serotonergic system in regulating extrapyramidal motor functions. 2399 48

Drugs acting through 5-hydroxytryptamine (serotonin or 5-HT) systems modulate memory and its alterations, although the mechanisms involved are poorly understood. 5-HT drugs may present promnesic and/or antiamnesic (or even being amnesic) effects. Key questions regarding 5-HT markers include whether receptors directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis; hence, the major aim of this article was to examine recent advances in emergent targets of the 5-HT systems for memory formation and memory alterations. Recent reviews and findings are summarized, mainly in the context of the growing notion of memory deficits in brain disorders (e.g., posttraumatic stress disorder, mild cognitive impairment, consumption of drugs, poststroke cognitive dysfunctions, schizophrenia, Parkinson disease, and infection-induced memory impairments). Mainly, mammalian and (some) human data were the focus. At least agonists and antagonists for 5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors as well as serotonin uptake inhibitors seem to have a promnesic and/or antiamnesic effect in different conditions and 5-HT markers seem to be associated to neural changes. Available evidence offers clues about the possibilities, but the exact mechanisms remain unclear. For instance, 5-HT transporter expression seems to be a reliable neural marker related to memory mechanisms and its alterations.
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PMID:5-HT systems: emergent targets for memory formation and memory alterations. 2425 45

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.
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PMID:Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease. 2467 33

Parkinson's disease (PD) is a common, late-onset neurodegenerative disorder that shows progressive extrapyramidal motor disorders (e.g., bradykinesia, resting tremors, muscle rigidity and postural instability) and various non-motor symptoms (e.g., cognitive impairment, mood disorders, autonomic dysfunction and sleep disorders). While dopaminergic agents such as L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine D2 agonists are widely used for the treatment of PD, there is still high clinical unmet need for novel medications that overcome the limitations of current therapies. Evidence is now accumulating that the serotonergic nervous system is involved in the pathophysiological basis of PD and can provide benefits in the treatment of PD through its diverse functions. Among 5-HT receptor subtypes, 5-HT1A, 5-HT2, 5-HT3 and 5-HT6 receptors play an important role in modulating extrapyramidal motor disorders. In addition, 5-HT1A, 5-HT2, 5-HT3, 5-HT4 and 5-HT6 receptors are implicated in modulation of cognitive impairment, mood disorders (e.g., depression and anxiety) and/or psychosis, which are frequently observed in patients with PD. Specifically, stimulation of 5-HT1A receptors seems to be effective for multiple PD symptoms including parkinsonism, L-DOPA-induced dyskinesia, cognitive impairment, mood disorders and neurodegeneration of dopamine neurons. Blockade of 5-HT2 receptors is also likely to improve parkinsonism, depressive mood and cognitive impairment. In addition, it was recently demonstrated that 5-HT2A inverse agonists can alleviate PD psychosis. All these findings emphasize the therapeutic roles of the serotonergic system in PD and stimulate new insight into novel treatments by modulating 5-HT1A and 5-HT2 receptors.
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PMID:New insight into the therapeutic role of the serotonergic system in Parkinson's disease. 2645 57

Numerous studies have investigated the role of agmatine in the central nervous system and indicated neuroprotective properties. In addition to its potent antioxidant effects, agmatine is an endogenous neuromodulator and has wide spectrum molecular actions on different receptor subtypes (NMDA, Imidazoline 1-2, alpha-2 adrenoreceptor, 5-HT2a, 5-HT3) and cellular signaling pathways (MAPK, PKA, NO, BDNF). Although the neuroprotective effects of agmatine demonstrated in experimental Parkinson's disease model, the effects of agmatine with the aspect of neuroplasticity and possible signaling mechanisms behind agmatine actions have not been investigated. Herein, in this study, we investigated the role of the of agmatine on rotenone-induced Parkinson's disease model. Agmatine at the dose of 100 mg/kg i.p., was mitigated oxidative damage and alleviated motor impairments which were the results of the rotenone insult. Additionally, agmatine decreased neuronal loss, tyrosine hydroxylase immunoreactivity and increased cREB, BDNF and ERK1/2 expression in the striatum, which are crucial neuroplasticity elements of striatal integrity. Taken together, the present study expands the knowledge of molecular mechanisms behind neuroprotective actions of agmatine in Parkinson's disease, and as far as we have known, this is the first study to delineate agmatine treated activation of cellular pathways which are important elements in neuronal cell survival.
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PMID:Neuroprotective action of agmatine in rotenone-induced model of Parkinson's disease: Role of BDNF/cREB and ERK pathway. 3247 47


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