Protection of Striatal Neurons by Joint Blockade of D1 and D2 Receptor Subtypes in an in Vitro Model of Cerebral Hypoxia

Davis, Sue; Brotchie, Jonathan M.; Davies, Ioan

doi:10.1006/exnr.2002.7926

Cited by 12 publications

(6 citation statements)

References 44 publications

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“…24,25 In addition, receptor-mediated mechanisms have been proposed to explain dopamine-induced neurotoxicity and the possible neuroprotective effects of dopamine D1 and D2 receptor antagonists have been investigated in several studies. 26 In our TTC staining experiments, both SCH23390 (D1 receptor antagonist) and metoclopramide (D2 receptor antagonist) failed to reduce OGD-induced damage and did not revert the enhanced toxicity caused by linopirdine, suggesting that, in our model, brain damage occurred in a dopamine receptor-independent manner. These results are not surprising, since conflicting evidence are present in the literature; indeed, while some studies failed to show neuroprotection by D1 and D2 receptor antagonists, others found that receptor stimulation (mainly the D2 subtype) reduced neuronal damage by blocking the apoptotic pathway (for a comprehensive review, see Bozzi and Borrelli 27 ).…”

Section: Discussionmentioning

confidence: 61%

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Barrese

Taglialatela

Greenwood

et al. 2015

J Cereb Blood Flow Metab

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Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since K v 7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The K v 7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The K v 7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an~6-fold decrease in K v 7.2 transcript, while levels of mRNAs encoding for other K v 7 subunits were unaffected; western blot experiments showed a parallel reduction in K v 7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for K v 7.2 in modulating ischemia-evoked caudate damage.

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Section: Discussionmentioning

confidence: 61%

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Barrese

Taglialatela

Greenwood

et al. 2015

J Cereb Blood Flow Metab

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Section: Da and Excitotoxicitymentioning

confidence: 99%

The role of dopamine in huntington's disease

Cepeda

Murphy

Parent

et al. 2014

Progress in Brain Research

135

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Alterations in dopamine (DA) neurotransmission in Parkinson’s disease are well-known and widely studied. Much less is known about DA changes that accompany and underlie some of the symptoms of Huntington’s disease (HD), a dominant inherited neurodegenerative disorder characterized by chorea, cognitive deficits and psychiatric disturbances. The cause is an expansion in CAG (glutamine) repeats in the HTT gene. The principal histopathology of HD is the loss of medium-sized spiny neurons (MSNs) and, to a lesser degree, neuronal loss in cerebral cortex, thalamus, hippocampus and hypothalamus. Neurochemical, electrophysiological and behavioral studies in HD patients and genetic mouse models suggest biphasic changes in DA neurotransmission. In the early stages DA neurotransmission is increased leading to hyperkinetic movements that can be alleviated by depleting DA stores. In contrast, in the late stages DA deficits produce hypokinesia that can be treated by increasing DA function. Alterations in DA neurotransmission affect glutamate receptor modulation and could contribute to excitotoxicity. The mechanisms of DA dysfunction, in particular the increased DA tone in the early stages of the disease, are presently unknown but may include initial upregulation of DA neuron activity caused by the genetic mutation, reduced inhibition resulting from striatal MSN loss, increased excitation from cortical inputs, and DA autoreceptor dysfunction. Targeting both DA and glutamate receptor dysfunction could be the best strategy to treat HD symptoms.

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“…However, an exclusive role for D1 receptor activation in mediating MSN degeneration is contradicted by evidence that blocking D2 receptor stimulation significantly reverses DA potentiation of mutant huntingtin-induced MSN cell death (Charvin et al, 2005). As cultured striatal neurons can be protected by antagonism of D1 and D2 receptors, it is possible that both D1 and D2 receptor activation might contribute to neurotoxicity (Davis et al, 2002; Bozzi and Borrelli, 2006). Thus, the exact nature of DA and NMDA interactions are dynamic and complex, indicating a need for further investigation into the differential effects of D1 and D2 activation on GLU signaling in the HD striatum.…”

Section: Da and Glu Receptor Interactions In Hdmentioning

confidence: 99%

Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility

et al. 2013

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Dopamine (DA) plays an essential role in the control of coordinated movements. Alterations in DA balance in the striatum lead to pathological conditions such as Parkinson's and Huntington's diseases (HD). HD is a progressive, invariably fatal neurodegenerative disease caused by a genetic mutation producing an expansion of glutamine repeats and is characterized by abnormal dance-like movements (chorea). The principal pathology is the loss of striatal and cortical projection neurons. Changes in brain DA content and receptor number contribute to abnormal movements and cognitive deficits in HD. In particular, during the early hyperkinetic stage of HD, DA levels are increased whereas expression of DA receptors is reduced. In contrast, in the late akinetic stage, DA levels are significantly decreased and resemble those of a Parkinsonian state. Time-dependent changes in DA transmission parallel biphasic changes in glutamate synaptic transmission and may enhance alterations in glutamate receptor-mediated synaptic activity. In this review, we focus on neuronal electrophysiological mechanisms that may lead to some of the motor and cognitive symptoms of HD and how they relate to dysfunction in DA neurotransmission. Based on clinical and experimental findings, we propose that some of the behavioral alterations in HD, including reduced behavioral flexibility, may be caused by altered DA modulatory function. Thus, restoring DA balance alone or in conjunction with glutamate receptor antagonists could be a viable therapeutic approach.

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Protection of Striatal Neurons by Joint Blockade of D1 and D2 Receptor Subtypes in an in Vitro Model of Cerebral Hypoxia

Cited by 12 publications

References 44 publications

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

The role of dopamine in huntington's disease

Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility

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Protection of Striatal Neurons by Joint Blockade of D1 and D2 Receptor Subtypes in an in Vitro Model of Cerebral Hypoxia

Cited by 12 publications

References 44 publications

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Protective Role of Kv7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

The role of dopamine in huntington's disease

Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility

Contact Info

Product

Resources

About

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices

Protective Role of K_v7 Channels in Oxygen and Glucose Deprivation-Induced Damage in Rat Caudate Brain Slices