Pathophysiology of motor response complications in Parkinson's disease: Hypotheses on the why, where, and what

Metman, Leo Verhagen; Konitsiotis, Spiros; Chase, Thomas N.

doi:10.1002/1531-8257(200001)15:1<3::aid-mds1003>3.0.co;2-e

Cited by 89 publications

(46 citation statements)

References 58 publications

(57 reference statements)

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“…However, with the progression of PD, presynaptic and postsynaptic derangements in nigrostriatal DA transmission preclude this restoration (40), and L-DOPA pharmacotherapy now elicits both involuntary movements and motor fluctuations (41). The essential underlying mechanism would be an excessive and pulsatile stimulation of both D1 and D2 receptors (42), conceivably causing overactivity of dSPNs and underactivity of iSPNs (4). Studies in both rodent and nonhuman primate models of LID have prompted the hypothesis that overactivity of dSPNs is the actual culprit in LID (33-35).…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Alcacer¹,

Andreoli²,

Sebastianutto³

et al. 2017

Journal of Clinical Investigation

111

115

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Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Alcacer¹,

Andreoli²,

Sebastianutto³

et al. 2017

Journal of Clinical Investigation

111

115

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“…We assumed that this difference might be because movement controlling circuitry contains various neurotransmitters and neuromodulators from both dopaminergic neurons and non-dopaminergic neurons, presenting motor response complications. 17,18) Reports have suggested that acute heat stress upregulates dopamine in several brain regions 3,19) and the excess dopamine must be metabolized. 20) Dopamine forms DOPAC and HVA via the action of catechol-O-methyltransferase and monoamine oxidase.…”

Section: Discussionmentioning

confidence: 99%

Repeated Heat Exposure Impairs Nigrostriatal Dopaminergic Neurons in Mice

Kim

Park

et al. 2013

Biological & Pharmaceutical Bulletin

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Environmental heat stress is associated with physical stress responses, including changes in monoamines, protein expression, and neuronal circuits and damage to neurons in the brain. This study determined the effects of heat stress on the nigrostriatal dopaminergic system based on behavioral, histological, and neurochemical analyses. To evaluate behavioral changes after heat exposure, we subjected mice to the pole and open field tests. The data suggested that heat stress for 7 d significantly impaired movement. Then, we conducted a histological analysis using tyrosine hydroxylase (TH) immunoreactivity in the striatum and substantia nigra (SN). Heat stress induced a significant deficit in TH-positive fibers and cells after 14-and 21-d exposure, respectively. We also measured the striatal dopamine (DA), 4-hydroxy-3-methoxy-phenylacetic acid, and 3,4-dihydroxyphenylacetic acid levels. The data suggested that DA turnover rate increased with heat exposure in a time-dependent manner, resulting in the significant decrease of DA after 28 d. Moreover, the expression of heat shock protein 70 (HSP70) was increased in the mouse SN with up to 14-d heat exposure, but decreased after 21 d of the stress. And glucose-regulated protein 78 (GRP78) was gradually increased in the mouse SN with 28-d heat exposure. The caspase-3 activity was also increased after 14-d heat exposure. These findings are the first evidence that repeated heat stress impairs nigrostriatal dopaminergic neurons, motor function, and DA availability with changes of HSP70 and GRP78 expressions and caspase-3 activity in mice.Key words repeated heat stress; dopaminergic neuron; heat shock protein 70; glucose-regulated protein 78; caspase-3 Extreme environmental temperatures induce systemic metabolic disorders accompanied by hyperthermia, behavioral, physiological, and biochemical changes, which might be considered pathophysiological indices for assessing heat stress.

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“…NMDA receptor hyperactivity has been associated with a variety of central nervous system disorders (Rothman and Olney, 1986;Lipton and Rosenberg, 1994;Metman et al, 2000). Despite efforts to design effective NMDA receptor antagonists, these often failed in clinical trials due to intolerable psychotic effects of completely blocking NMDA receptor signaling (Albers et al, 1999;Morris et al, 1999;Davis et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Ca 21 entry through NMDA receptors is required during neuronal development for synapse formation and throughout life for synaptic maintenance and plasticity (Bliss et al, 2003). NMDA receptors are key mediators of glutamate excitotoxicity, and NMDA receptor hyperactivity has been associated with many neurologic conditions, including ischemic stroke, epilepsy, and neurodegenerative disorders (Rothman and Olney, 1986;Lipton and Rosenberg, 1994;Metman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GluN2A-Containing N-Methyl-d-Aspartate Receptors by 2-Naphthoic Acid

Popescu

2013

Mol Pharmacol

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N-Methyl-D-aspartate (NMDA) receptors mediate excitatory synaptic transmission in the central nervous system and play important roles in synaptic development and plasticity, but also mediate glutamate neurotoxicity. Recently, 2-naphthoic acid (NPA) and its derivatives have been identified as allosteric, noncompetitive NMDA receptor inhibitors. The selectivity of NPA derivatives among NMDA receptor subtypes was mapped structurally to the ligand-binding domain, and was proposed to be mediated by residues on the S1 segment. To delineate the kinetic mechanism by which NPA inhibits NMDA receptor activity, we examined its effects on the NMDA receptor gating reaction. Using whole-cell patch clamping on human embryonic kidney 293 cells expressing recombinant NMDA family of glutamate receptor subunits, GluN1/GluN2A, we found that NPA has a 50% inhibitory effect at 1.9 mM. Further, from onechannel current recordings, we found that 4 mM NPA caused a 62% decrease in open probability by decreasing mean open time 2.5-fold and by increasing mean closed time 2-fold. Kinetic modeling suggested that NPA binding stabilized NMDA receptor closed states and increased the energy barriers toward open states, causing NMDA receptors to dwell longer in pre-open states along the activation pathway. The reaction mechanisms we derived provide quantitative insight into the inhibitory mechanism of NPA and help anticipate its effects on GluN1/ GluN2A receptors during both physiologic and pathologic activation modalities.

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Pathophysiology of motor response complications in Parkinson's disease: Hypotheses on the why, where, and what

Cited by 89 publications

References 58 publications

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Repeated Heat Exposure Impairs Nigrostriatal Dopaminergic Neurons in Mice

Inhibition of GluN2A-Containing N-Methyl-d-Aspartate Receptors by 2-Naphthoic Acid

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