CANNABINOIDS IN THE TREATMENT OF NEURODEGENERATIVE DISORDERS

Patricia Staquet and Aikaterina Skokotas

Rosemont College, Rosemont, PA 19010

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Abstract

Throughout this project, I will explore the potential properties that cannabinoids possess for treating particular neurodegenerative disorders. This paper will include: a brief history of how cannabinoids have been used medicinally for centuries and have transitioned into its now modern day status; a definition of the two classes of cannabinoids, both endocannabinoids and phytocannabinoids; the mechanism of cannabinoids in the human body; the goals of current research on how cannabinoids are being used to treat the neurodegenerative diseases of Alzheimer's disease, Huntington’s disease, Parkinson’s disease, and Multiple Sclerosis; and finally a discussion of future directions for cannabinoid research.

History of Cannabinoids

Figure 1- Timeline of Cannabis Modern History

This timeline displays the history of the Cannabis plant spanning from 1839 to present day.

What are Endocannabinoids?

Figure 2 - Chemical Structures of Endocannabinoids

These images depict the chemical structures of endocannabinoids 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (AEA, also known as anandamide).

What are Phytocannabinoids?

Figure 3- Chemical Structures of Phytocannabinoids

These images depict the chemical structures of the phytocannabinoids trans-Δ9 - tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD).

Endocannabinoid System (ECS)

• Responsible for the homeostatic regulation of cells in the human body
• Comprises lipid-signaling endogenous ligands named endocannabinoids (eCBs), biosynthesizing and degrading enzymes, and their associated receptors and is broadly distributed in the central and peripheral nervous systems

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Cannabinoid Receptors

Figure 4- Schematic outline for some of the possible receptors for phytocannabinoids and endocannabinoids.

The prototypical G-protein coupled receptors for cannabinoids are CB1 and CB2, but GPR55 has been suggested to be a possible third cannabinoid receptor. CB1 and CB2 are negatively coupled to adenylate cyclase (AC) via Gi/o, while GPR55 is potentially linked to the IP3/DAG/Ca2+ system. Cannabinoids are also known to bind to transient receptor potential channels such as TRPV1, TRPV2 and TRPA1. Possible downstream effects include the regulation of genes and ion channel activity (A-type K+ channels).

Cannabinoid Receptors

Figure 5- Summary of the different mechanisms proposed for the neuroprotection exerted by cannabinoids.

Abbreviations: eCBs, endocannabinoids; IL, interleukin; PPAR, peroxisome proliferator-activated receptor; ROS, Reactive oxygen species; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid type 1.

Goal of Phytocannabinoid Therapies

Figure 6- The potential neuroprotection offered by the endocannabinoid system.

The ECS has revealed neuroprotective effects in some experimental models of neurodegenerative diseases.

Alzheimer's Disease (AD)

• What is it?
• An age-related neurodegenerative disease in which a pathological hallmark is the onset of neurofibrillary tangles and amyloid beta plaques in the brain
• Symptoms:
• Progressive decline in cognition and memory
• Concomitant activation of microglia in plaque filled regions
• Neuroinflammation and oxidative stress
• Cell death occurs

Cannabinoids and Alzheimer's Disease

• CB1 receptor expression is high in basal ganglia and hippocampus, where β-amyloid plaques tend to occur most often in AD
• Neuronal CB1 expression is ↓
• Expression of CB1 and CB2 expressing microglia is ↑
• CBD could protect from excitotoxicity and neuroinflammation by relieving secondary pathologies associated with AD

Cannabinoids and AD Clinical Results

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• Δ9 -THC
• In a study, Eubanks and colleagues found that Δ9 -THC competitively inhibits Acetylcholinesterase activity and reduces Aβ aggregation in vitro.
• The CB1 receptor agonists anandamide and noladin ether are capable of inhibiting Aβ toxicity in a differentiated human teratocarcinoma cell line Ntera 2/ cl-D1 neurons
• This may be linked to a reduction in glutamate release through downregulation of N-type Ca channel activity, or an upregulation of K-channel activity, both of which are associated with reduced synaptic transmitter release

Cannabinoids and AD Clinical Results

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• 2.5 mg dronabinol
• 6-week crossover trial appeared to reduce disturbed behaviors in 12 patients, as measured by the Cohen-Mansfield Agitation Inventory

Huntington’s Disease (HD)

• What is it?
• HD is a rare autosomal-dominant progressive neurodegenerative disorder caused by a mutation in the IT15 gene that encodes the huntingtin protein (HTT)
• Symptoms
• Abnormal involuntary muscle movements
• Progressive decline in cognition and memory
• Irritability, depression and other mood changes

Cannabinoids and Huntington’s Disease

• ↓ in CB1 receptor levels prior to the neurodegeneration of MSNs and the onset of motor symptoms
• Inhibition of CB1 transcription mediated by the mutant HTT
• Activation of CB1 cannabinoid receptors by cannabinoid agonists would be expected to lead to:
• ↓ glutamate release
• limit excitotoxicity

Cannabinoids and HD Clinical Results

• A 6-week crossover trial evaluated cannabidiol (a total of 10 mg/kg over two doses daily) for chorea in 15 patients with Huntington’s disease.
• No significant difference between placebo and cannabidiol on chorea severity measured by the Marsden and Quinn’s Chorea Severity Scale
• 10-week placebo-controlled crossover trial, nabilone (1 or 2 mg)
• Showed significant treatment effect as measured by the total motor and chorea score on the Unified Huntington’s Disease Rating Scale
• Nabiximols (up to 12 sprays/day)
• No significant treatment effect was reported on the UHDRS, in a sample of 25 patients

Parkinson’s Disease (PD)

• What is it?
• An age-related neurodegenerative disease in which a pathological hallmark is the accumulation of α-synuclein aggregates and the degeneration of dopaminergic neurons leading to dopamine depletion
• Symptoms
• Motor alterations
• Bradykinesia, resting tremors, rigidity and postural instability
• Dementia
• Depression

Cannabinoids and Parkinson’s Disease

• CBD can ↓ neuroinflammation
• CB1 activation can diminish dopaminergic neuronal damage
• Leads to a ↓ of microglial activation
• CBD can ↓ excitotoxicity
• Occurs due to the overstimulation of glutamatergic receptors
• CBD can regulate glutamate release, thus providing a way to reduce excitotoxicity

Cannabinoids and PD Clinical Results

• 0.03 mg/kg nabilone
• Early crossover trial involving 9 Parkinson’s disease patients with dyskinesia
• Significantly improved dyskinesia as indexed by the Rush dyskinesia disability scale.
• Titrated cannador up to 0.25 mg/kg THC or placebo
• 4-week dose escalation crossover trial, 19 Parkinson’s disease patients with levodopa-induced dyskinesia
• Cannador failed to show any significant treatment effect on the primary outcome (Unified Parkinson’s Disease Rating Scale (UPDRS) dyskinesia items) as well as secondary measures such as motor symptoms and quality of life (39-item Parkinson’s disease questionnaire, PDQ-39)

Cannabinoids and PD Clinical Results

• Cannabidiol (75 mg/day or 300 mg/day) or placebo
• Placebo-controlled trial, 21 patients with Parkinson’s disease were randomized to receive cannabidiol or placebo for 6 weeks
• No statistical significant difference between the groups on the UPDRS
• However, a significant improvement was reported for PDQ-39, particularly the activities of daily living and stigma subscale for the 300 mg/day cannabidiol group

Multiple Sclerosis (MS)

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• What is it?
• An autoimmune disease that is characterized by demyelination and degeneration of motor neurons
• Symptoms:
• Neuropathic pain
• Aberrant neuronal activity
• Debilitating & painful muscle spasms

Cannabinoids and Multiple Sclerosis

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• In patients with MS:
• Endocannabinoid levels in the circulating plasma ↑
• CBD has been shown to be capable of relieving neuropathic pain associated with MS
• Neuroprotective role for CB1

Cannabinoids and MS Clinical Results

• Δ9 -THC and CBD whole plant cannabis-based medicinal extracts
• Well-constructed, randomized, double blind clinical trials were conducted on a cohort of 160 patients with MS resulted in improved scores on symptoms such as spasticity, spasms, tremor, pain and bladder control
• However statistical significance was lacking
• Δ9 - THC:CBD extract (nabiximols)
• A meta-analysis of three studies evaluated a total of over 660 patients with spasticity
• The authors concluded that nabiximols reduced spasticity beyond what would occur by placebo alone

Conclusion

• Legalization of cannabis for medicinal use and recreational purposes will ease the restrictions for research
• Future Directions:
• Overcoming unwanted psychotropic side effects of THC, which limit its capacity as a therapeutic agent
• Cannabinoid receptor sites need to be fully identified and properly characterized
• Intensive research identifying the molecular targets and signaling mechanisms of cannabinoids could eventually lead to highly selective cannabimimetics

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