More recently, the importance of neuroinflammation in Parkinson's Disease (PD) pathophysiology has also emerged. Indeed, activated microglia have been described in close proximity to degenerating dopamine neurons in individuals with PD, and activation of microglia into the substantia nigra has been shown to cause selective destruction of dopamine neurons.

Furthermore, experimental parkinsonism, induced by neurotoxins specific to dopamine neurons, is coupled with the activation of nigral and striatal microglia and with the production of proinflammatory molecules. In addition, in models of PD, inhibition of microglia is neuroprotective.

As in Alzheimer Disease (AD), polymorphisms of some cytokines have been identified as risk factors for PD, whereas epidemiological studies have reported that chronic users of anti-inflammatory drugs have a decreased risk for PD.

By contrast, recent data have shown that prior delivery of a peripheral, pro-inflammatory stimulus induces neuroprotection in a rodent model of PD. This protective effect is paralleled by a concomitant reduction in the associated microglial response and moderate, transient increases in cytokine levels at the sites of neurodegeneration. Therefore, modulation of the neuroprotective effect of peripheral inflammation might be exploited for improving the treatment of PD.

Furthermore, more recent papers highlight the role of endocannabinoids in Parkinson:

The components of the endocannabinoid (ECB) system are highly expressed at different levels in the basal ganglia neural circuit where they bidirectionally interact with dopaminergic, glutamatergic and GABAergic signaling systems. In particular, at synapses linking cortical and striatal neurons, endocannabinoids (ECBs) are known to critically modulate synaptic transmission and to mediate the induction of a particular form of synaptic plasticity, the long-term depression.

The evidence that ECBs play a central role in regulating basal ganglia physiology and motor function and the profound modifications occurring in ECB signaling after dopamine depletion in both experimental models of PD and patients suffering from the disease, provide support for the development of pharmacological compounds targeting the ECB system as symptomatic and neuroprotective therapeutic strategies for PD.^[1] 

And: 

There is evidence that cannabinoid-based medicines that are selective for different targets in the cannabinoid signalling system (e.g. receptors, inactivation mechanism, enzymes) might be beneficial in basal ganglia disorders, namely Parkinson's disease (PD) and Huntington's disease (HD).

... extensive biochemical, anatomical, physiological and pharmacological studies have demonstrated that: (i) the different elements of the cannabinoid system are abundant in basal ganglia structures and they are affected by these disorders; (ii) the cannabinoid system plays a prominent role in basal ganglia function by modulating the neurotransmitters that operate in the basal ganglia circuits, both in healthy and pathological conditions; and (iii) the activation and/or inhibition of the cannabinoid system is associated with important motor responses that are maintained and even enhanced in conditions of malfunctioning and/or degeneration.  ^[2] 

And:

Cannabinoid-based medicines have been proposed as clinically promising therapies in Parkinson's disease (PD), given the prominent modulatory function played by the cannabinoid signaling system in the basal ganglia.

... certain cannabinoid agonists have been proposed to serve as neuroprotective molecules in PD, given their well-demonstrated capability to reduce excitotoxicity, calcium influx, glial activation and, in particular, oxidative injury that cooperatively contribute to the degeneration of nigral neurons.

However, the potential of cannabinoid-based medicines in PD have been still scarcely studied at the clinical level despite the existence of solid and promising preclinical evidence. Considering the relevance of these preclinical data, the need for finding treatments for motor symptoms that may be alternative to classic dopaminergic replacement therapy, and the lack of efficient neuroprotective strategies in PD, we believe it is of major interest to develop further studies that allow the promising expectations generated for these molecules to progress from the present preclinical evidence towards a real clinical application.^[3] 

With the availability of palmitoylethanolamide (Normast), one of the most important endocannabinoids, as a foodsupplement, small trials in PD could start. The more so, as this molecule is safe and has been administered to more than 800.000 patients world wide without any clinical problems.

Palmitoylethanolamide both has neuroprotective properties, analgesic properties as well as anti-inflammatory properties.

Jan M. Keppel Hesselink, MD, PhD, april 2011 

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