Author Archives: David Worrell

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease.

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Δ9-THC directly protected human neuronal cells in a laboratory model of Parkinson’s disease from three different Parkinson’s-related toxins: MPP+, lactacystin, and paraquat. Across the experiments, THC reduced toxin-induced cell injury, oxidative stress, and apoptosis.

The researchers found that this neuroprotective effect was linked strongly to PPARγ activation. Blocking PPARγ reduced THC’s protective effects, while THC increased PPARγ expression in injured cells, pointing to this pathway as an important part of the mechanism.

These findings show that THC acted directly on vulnerable human neuronal cells in this Parkinson’s disease model, not just on symptoms. The study adds evidence that THC may have neuroprotective potential in conditions involving oxidative stress, mitochondrial dysfunction, and neuronal loss.

“Aims: Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson’s disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC.

Methods: Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed.

Results: We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation.

Conclusions: We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation.”

https://www.ncbi.nlm.nih.gov/pubmed/22236282

“In conclusion, we have demonstrated up-regulation of the CB1 receptor in a human cell culture model of PD, as well as a direct neuroprotective effect of the phytocannabinoid, Δ9-THC, not mediated by the CB2 receptor. Although a CB1 receptor-mediated effect cannot totally be excluded, we propose that activation of PPARγ leading to antioxidant effects is highly relevant in mediating the neuroprotection afforded by Δ9-THC in our model.”

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2990.2011.01248.x/full

Need this THC study explained? thcXplained.com

Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease

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“Previous findings have indicated that a cannabinoid, such as Δ(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson’s disease (PD).

…Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms…

Conclusion

In summary, given its antioxidant properties and its ability to activate CB2 but block CB1 receptors at a dose of 2 mg·kg−1, Δ9-THCV seems to have an interesting and therapeutically promising pharmacological profile. Thus, in contrast to other phytocannabinoids that have been investigated to date, it shows promise both for the treatment of disease progression in PD and for the relief of PD symptoms. This represents an important advance in the search for potential novel anti-parkinsonian agents, since Δ9-THCV administered alone or in combination with CBD may provide a much needed improved treatment for PD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165958/

Therapeutic effects of Delta9-THC and modafinil in a marmoset Parkinson model.

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Abstract

“Current therapies for Parkinson’s disease (PD) like l-dopa and dopamine (DA) agonists have declined efficacy after long term use. Therefore, research towards supplementary or alternative medication is needed. The implementation in PD can be expedited by application of compounds already used in the clinic. In this study the therapeutic effects of the psychoactive compounds Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and modafinil were tested in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-marmoset model for PD. The anti-parkinson effects of Delta(9)-THC (4 mg/kg) and modafinil (100 mg/kg) in parkinsonian marmosets were assessed with two behavioral rating scales covering parkinsonian symptoms and involuntary movements and two test systems assessing the locomotor activity and hand-eye coordination. Delta(9)-THC improved activity and hand-eye coordination, but induced compound-related side-effects. Modafinil improved activity and observed parkinsonian symptoms but not hand-eye coordination. It can be concluded that both compounds have therapeutic values and could supplement existing therapies for PD.”

http://www.ncbi.nlm.nih.gov/pubmed/18222654

Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties.

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Abstract

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/17196181

Cannabinoids and Parkinson’s disease.

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Abstract

“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. Supporting this pharmacological potential, the cannabinoid signaling system experiences a biphasic pattern of changes during the progression of PD. Thus, early and presymptomatic stages, characterized by neuronal malfunctioning but little evidence of neuronal death, are associated with desensitization/downregulation of CB(1) receptors. It was proposed that these losses may be part of the pathogenesis itself, since they can aggravate different cytotoxic insults which are controlled in part by cannabinoid signals, mainly excitotoxicity but also oxidative stress and glial activation. By contrast, intermediate and, in particular, advanced stages of parkinsonism characterized by a profound nigral degeneration and occurrence of major parkinsonian symptoms (e.g. bradykinesia), are associated with upregulatory responses of CB(1) receptors, possibly CB(2) receptors too, and the endocannabinoid ligands for both receptor types. This would explain the motor inhibition typical of this disease and the potential proposed for CB(1) receptor antagonists in attenuating the bradykinesia typical of PD. In addition, 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.”

http://www.ncbi.nlm.nih.gov/pubmed/19839934

An overview of Parkinson’s disease and the cannabinoid system and possible benefits of cannabinoid-based treatments.

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Abstract

“Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder with a heterogeneous clinical picture and a variable rate of progression. PD is characterized by degeneration of the pigmented neuromelanin bearing cells of the pars compacta of the substantia nigra that leads to a severe dopaminergic denervation of the striatum. Current treatments for PD rely on dopamine replacement therapy, most commonly with the dopamine precursor levodopa. Despite the many recent advances in the symptomatic treatment of PD, there is still no realistic prospect for a cure. In recent years, new data support the idea of a relevant role for the cannabinoid system in PD. As cannabinoids have neuroprotective properties, they have been proposed as potentially useful neuroprotective substances in PD, as well as to alleviate some symptoms in specific circumstances (i.e. parkinsonian tremor associated with overactivity to the subthalamic nucleus; levodopa-induced dyskinesia). By contrast, CB(1) receptor antagonists might be useful to reduce bradykinesia in patients refractory to classic levodopa treatment. The present article will review all data about the relationship between PD and the cannabinoid system including: i) the usefulness of cannabinoid-related compounds to alleviate some PD symptoms; ii) that cannabinoid-based compounds might provide protection against the progression of neuronal injury characteristic of this disease; iii) the influence of cannabinoids on local inflammatory events associated with the pathogenesis in PD. Collectively, all these evidence support that the management of the cannabinoid system might represent a new approach to the treatment of PD.”

http://www.ncbi.nlm.nih.gov/pubmed/17168732

The endocannabinoid system in Parkinson’s disease.

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Abstract

“Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder of largely unknown etiology caused by a pathological cascade resulting in the degeneration of midbrain dopaminergic neurons of the substantia nigra pars compacta (SNpc) projecting to the nucleus striatum, the main input station of the basal ganglia neuronal circuit. 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.”

http://www.ncbi.nlm.nih.gov/pubmed/18781984

Enhancing activity of marijuana-like chemicals in brain helps treat Parkinson’s symptoms in mice, Stanford study finds

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“Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson’s disease. In a study published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson’s.

“This study points to a potentially new kind of therapy for Parkinson’s disease,” said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. “Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease.”

Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study’s lead author, combined a drug already used to treat Parkinson’s disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson’s, the mice went from being frozen in place to moving around freely in 15 minutes. “They were basically normal,” Kreitzer said.”

https://med.stanford.edu/news/all-news/2007/02/enhancing-activity-of-marijuana-like-chemicals-in-brain-helps-treat-parkinsons-symptoms-in-mice-stanford-study-finds.html

“Brain chemicals may aid treatment of Parkinson’s”  http://news.stanford.edu/news/2007/february14/med-brain-021407.html

Natural brain substance linked to Parkinson’s symptoms

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“Neuroscientists have found that a substance similar to the active ingredient in marijuana but produced naturally in the brain helps to control mobility — and may offer a novel target for treating Parkinson’s disease.

The findings by Stanford University researchers, reported in the latest issue of the journal Nature, show how marijuana-like “endocannabinoids” — one of the many chemicals used in the brain to transmit signals — form part of the neural machinery that directs normal physical movement.

A shortage of the endocannabinoids, the scientists found, can knock the system out of balance to produce the characteristic tremor, rigidity and other mobility problems of Parkinson’s disease patients…”

Read more; http://www.sfgate.com/health/article/Natural-brain-substance-linked-to-Parkinson-s-2650879.php