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

We have recently demonstrated that two plant-derived cannabinoids, Delta9-tetrahydrocannabinol and cannabidiol (CBD), are neuroprotective in an animal model of Parkinson's disease (PD), presumably because of their antioxidant properties. To further explore this issue, we examined the neuroprotective effects of a series of cannabinoid-based compounds, with more selectivity for different elements of the cannabinoid signalling system, in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine. We used the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 receptor agonist HU-308, the non-selective agonist WIN55,212-2, and the inhibitors of the endocannabinoid inactivation AM404 and UCM707, all of them administered i.p. Daily administration of ACEA or WIN55,212-2 did not reverse 6-hydroxydopamine-induced dopamine (DA) depletion in the lesioned side, whereas HU-308 produced a small recovery that supports a possible involvement of CB2 but not CB1 receptors. AM404 produced a marked recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side. Possibly, this is caused by the antioxidant properties of AM404, which are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter, because UCM707, another transporter inhibitor devoid of antioxidant properties, did not produce the same effect. None of these effects were observed in non-lesioned contralateral structures. We also examined the timing for the effect of CBD to provide neuroprotection in this rat model of PD. We found that CBD, as expected, was able to recover 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion, but it failed to do that when the treatment started 1 week later. In addition, the effect of CBD implied an upregulation of mRNA levels for Cu,Zn-superoxide dismutase, a key enzyme in endogenous defenses against oxidative stress. In summary, our results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. In addition, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease.
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PMID:Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties. 1719 81

Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.
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PMID:Adenosine A2A receptors and basal ganglia physiology. 1764 43

In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.
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PMID:Long-term depression of cortico-striatal synaptic transmission by DHPG depends on endocannabinoid release and nitric oxide synthesis. 1786 68

Different classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoid-mediated synaptic modulation. HOWEVER, ENDOCANNABINOIDS HAVE A DUAL ROLE: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinson's disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial.The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration.
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PMID:Endocannabinoid signaling in midbrain dopamine neurons: more than physiology? 1930 43

The endocannabinoid system, including endogenous ligands ('endocannabinoids' ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G protein-coupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed.
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PMID:Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration. 1935 23

The endocannabinoid system (ECS) exerts important modulatory functions in the central nervous system (CNS), particularly the retrograde control of excitatory or inhibitory synapses, which enables this system to participate in the control of important neurobiological processes in healthy conditions. However, this physiological relevance acquires a maximal interest in neuropathological conditions affecting either the function or the structures of specific areas of the brain, conditions that have been associated with important changes in the activity of this modulatory system (e.g. losses of CB1 receptors (CB1R), up-regulation of CB2 receptors (CB2R), generation of endocannabinoids) that are susceptible to pharmacological adaptation. Among the group of brain disorders that have been associated with the endocannabinoid system, a special interest has been concentrated in various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and ischemia. These three disorders will be reviewed here from the perspective of the types of changes experienced by the cannabinoid signalling in humans and cellular or animal models, and from a possible usefulness of certain cannabinoid compounds to alleviate symptoms and/or to delay their progression.
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PMID:The endocannabinoid system in neuropathological states. 1936 11

In animal models of early Parkinson's disease (PD), motor deficits are accompanied by excessive striatal glutamate release. Blockade of group I metabotropic glutamate receptors (mGluRs), endocannabinoid degradation and nitric oxide (NO) synthesis combats PD symptoms. Activation of group I mGluRs with the specific agonist 3,5-dihydroxyphenylglycine (DHPG) induces long-term depression of corticostriatal transmission (LTD(DHPG)) in the adult mouse striatum requiring NO synthesis downstream to cannabinoid CB1 receptor (CB1R) activation suggesting a dual role for LTD(DHPG): neuroprotective by down-regulation of glutamatergic transmission and, under certain circumstances, neurotoxic by release of NO. We report now that LTD(DHPG) undergoes a developmental switch from N-methyl-D-aspartate (NMDA)-receptor-dependent/CB1R-independent to NMDA receptor-independent/CB1R-dependent plasticity with NO playing an essential role for LTD(DHPG) at all developmental stages. The gain in function of CB1R is explained by their developmental up-regulation evaluated with real-time reverse transcription-polymerase chain reaction. These findings are relevant for the pathophysiology and therapy of PD as they link the activation of group I mGluRs, endocannabinoid release, and striatal NO production.
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PMID:Developmental alterations of DHPG-induced long-term depression of corticostriatal synaptic transmission: switch from NMDA receptor-dependent towards CB1 receptor-dependent plasticity. 1970 70

ESCs (embryonic stem cells) are potentially able to replace damaged cells in animal models of neural pathologies such as Parkinson's disease, stroke and spinal cord lesions. Nevertheless, many issues remain unsolved regarding optimal culturing procedures for these cells. For instance, on their path to differentiation in vitro, which usually involves the formation of EBs (embryoid bodies), they may present chromosomal instability, loss of pluripotency or simply die. Therefore, finding strategies to increase the survival of cells within EBs is of great interest. Cannabinoid receptors have many roles in the physiology of the adult body, but little is known about their role in the biology of ESCs. Herein, we investigated how two cannabinoid receptors, CB1 and CB2, may affect the outcome of ESCs aggregated as EBs. RT-PCR (reverse transcriptase-PCR) revealed that EBs expressed both CB1 and CB2 receptors. Aggregation of ESCs into EBs followed by 2-day incubation with a CB1/CB2 agonist reduced cell death by approximately 45%, which was reversed by a CB1 antagonist. A specific CB2 agonist also reduced cell death by approximately 20%. These data indicate that both cannabinoid receptors, CB1 and CB2, are involved in reducing cell death in EBs mediated by exogenous cannabinoids. No increase in proliferation, neural differentiation or changes in chromosomal stability was observed. This study indicates that cannabinoid signalling is functionally implicated in the biology of differentiating ESCs, being the first to show that activation of cannabinoid receptors is able to increase cell viability via reduction of cell death rate in EBs.
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PMID:Cannabinoids modulate cell survival in embryoid bodies. 1994 26

Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [(18)F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [(18)F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [(18)F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p=0.001 and p<0.0003, respectively). The number of TH(+) neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10(-6)). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p=4.10(-6)). In vivo [(18)F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex.
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PMID:In vivo type 1 cannabinoid receptor mapping in the 6-hydroxydopamine lesion rat model of Parkinson's disease. 2002 90

This study was designed to examine the type of changes experienced by the CB1 receptor, a key element of the cannabinoid signaling system, in the basal ganglia of different mouse mutants generated by deletion of specific genes associated with the development of Parkinson's disease in humans [PARK1 (alpha-synuclein), PARK2 (parkin) or PARK6 (PINK1)]. We observed that CB1 receptor-mRNA levels were significantly reduced in the caudate-putamen in the three models under examination when animals were analyzed at early phases (< or = 12 months of age). This decrease was, in general, associated with a reduction in CB1 receptor binding in the substantia nigra and the globus pallidus, particularly in the case of alpha-synuclein-deficient mice. By contrast, both parameters, mRNA levels and binding for the CB1 receptor, showed an elevation in the same areas when animals were analyzed at older ages, mainly in the case of the CB1 receptor binding in the substantia nigra. In summary, our data revealed the existence of a biphasic response for CB1 receptors, with losses at early phases, when dopaminergic dysfunction is possibly the major event that takes place, followed by upregulatory responses at advanced phases characterized by the occurrence of evident nigrostriatal pathology including neuronal death in some cases.
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PMID:Cannabinoid CB1 receptors are early downregulated followed by a further upregulation in the basal ganglia of mice with deletion of specific park genes. 2041 85


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