Neurodegenerative Disease Parkinson’s Disease
the co-factor biopterin necessary for tyrosine hydroxylase function.33 Gene therapy provides striatal neurons with the machinery to produce dopamine, obviating the need for exogenous L-DOPA delivery and providing a continuous supply of dopamine. This has been successfully demonstrated to protect against LID development in rodent and primate models of advanced PD34,35 are in progress.
and clinical trials Post-synaptic Plasticity
As dopaminergic innervation is lost, plastic changes occur at the post-synaptic membranes of striatal medium spinal neurons expressing D1 or D2 receptors. These are differentially altered again by the repeated pulsatile administration of L-DOPA.36
There
are substantial data pointing towards a close correlation between the severity of LID and post-synaptic changes at the receptor level, downstream kinases, at gene regulation and transcription, largely focused around the D1 receptor subtype.11,12,37–40
Pre-clinical
studies with dopamine D1 receptor agonists show both good antiparkinsonian and pro-dyskinetic effects, part of which may be attributed to their short half-lives, but also to the biochemical changes occurring at this receptor. D1 receptors are in fact G-protein-coupled receptors linked to G proteins, stimulating adenylate cyclase and activating gene transcription. With dopaminergic denervation and administration of L-DOPA, dopamine D1 receptors become more highly expressed and increasingly sensitive, the G-protein levels increasing, thereby altering activity through the whole signalling cascade.
Long-term dopamine D1 receptor sensitisation is controlled in part by G-protein receptor kinases (GRKs), which normally trigger receptor internalisation and halt the receptor response. GRK6, for example, is upregulated by MPTP administration to non-human primates and normalised by L-DOPA treatment.41
normalisation significantly reduces LID, probably through the process of increasing internalisation of the D1 receptor.42
Further down the receptor cascade, components of the RAS/ERK signalling pathway become hyperactive in response to D1 supersensitivity and inhibitors of ERK, or an intermediary in this pathway, significantly reduce the severity of LID.43–45
The importance
of these pathways is also that they are a point of convergence at which dopaminergic nigrostriatal and glutamatergic corticostriatal inputs to the medium spiny neurons are acting through co-localised dopaminergic and glutamatergic metabotropic receptors. Activation of the RAS/ERK pathway leads to phosphorylation of the GluR1 subunit on AMPA receptors located at the synapse promoting glutamatergic transmission.46
Further still down the cascade, the acetylation and phosphorylation states of histones H3 and H4 are altered (although reports are inconsistent as to the details).47–49
Dopamine D3 receptors that are co-expressed with D1 receptors on the direct pathway are increased in animal models of LID and may directly interact with them through intramembrane crosstalk.52 Nevertheless, in vivo reports are conflicting, suggesting either no effect or significant improvement on the effect of manipulating activity at the D3 receptor in LID, which may or may not be at the expense of the antiparkinsonian effect of L-DOPA.53–57
Dopamine D2 receptor agonists are effective at alleviating some of the symptoms of the motor disorder in early stages of the disease, partly because de novo therapies do not commonly induce significant levels of dyskinesia.58,59
Before concluding that D1 receptors are the
LID culprits, however, it must be considered that D2 receptor agonists can produce motor sensitisation60
and are capable of inducing
dyskinesia expression if L-DOPA priming has already taken place.61 Therefore, D2 receptors are not innocent bystanders concerning LID generation or expression.
Whether there are direct changes in D2 receptor expression in response to chronic L-DOPA administration is unclear,62
but there
are indications that D2 receptor mechanisms are altered and as such could be potential therapeutic targets. D2 receptors are negatively coupled through G-protein Gi/o to adenylate cyclase, the activity of the G-protein being controlled by the speed at which guanosine triphosphate is converted back into guanosine diphosphate. Regulators of G-protein signalling (RGS) are GTPases, which mediate this conversion, effectively influencing the speed of inactivation of the active α G-protein subunit. RGS9 is upregulated following chronic L-DOPA administration63
and is thought to reflect
an intrinsic compensation to the increase in D2 receptor activity. Despite this, further upregulation compromised the beneficial effects of L-DOPA.63
Reversing this
Microvascular Changes in L-DOPA-induced Dyskinesia
Maladaptive plasticity in LID is not restricted to neuronal activity but also includes the structural microenvironment of the basal ganglia. There is accumulating evidence of changes to the essential microvasculature in PD, accompanying both the progressive dopamine degeneration and the development of LID. Post-mortem studies of human PD brains have demonstrated pathological microvascular changes and altered levels of angiogenic cytokines in the basal ganglia.64–67
Recent experiments in rodents suggest that the microvascular changes may be attributable to dyskinesiogenic D1-receptor stimulation and activation of ERK1/2.43,68
These angiogenic vessels
may represent areas with blood–brain barrier leakage and thus local foci of high L-DOPA concentration that may further exacerbate the fluctuations of dopamine. Interestingly, drugs with well-known effects
Nevertheless, this is indicative of
chromatin rearrangements and thereby changes in transcriptional control. An example of these transcriptional changes is the persistent
upregulation of the immediate early gene ΔFosB in the striatum of dyskinetic rodent and non-human primates.11,50,51
This is indicative
of the long-term changes that cause the priming phenomena, meaning that dyskinesia can still be evoked after prolonged L-DOPA withdrawal. Experimental evidence suggests that it may be possible to ‘deprime’ the L-DOPA-treated striatum through suppression of these proteins.11,51
36
on vascular physiology, such as α2-adrenergic receptor antagonists and nicotine, have well-documented antidyskinetic efficacy in animal models of PD.69–71
This suggests that possible effects on the
microvasculature need to be taken into consideration when novel treatments for PD are evaluated.
Non-dopaminergic Modulators of Dyskinesia As mentioned above, striatal function is not only modulated by nigrostriatal dopaminergic inputs. Indeed glutamatergic, corticostriatal and acetylcholine interneurons also have modulatory influences and
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