REVIEW ON ACTIVITY OF CANNABIS TREATMENT ON PARKINSON’S DISEASE

REVIEW ON ACTIVITY OF CANNABIS TREATMENT ON PARKINSON’S DISEASE

Douglas Zorinmawia Chhakchhuak, G. Swetha Saniya Tabassum and Anjali Raj *

Department of Pharmacology, Pharmacy # 6/9, 1st Cross, Begur Road, Hongasandra, Bengaluru, Karnataka, India.

ABSTRACT: As new treatments and medication are growing rapidly, neurologists are also toward expanding treating patients with idiopathic Parkinson's disease and facing questions regarding cannabis as a treatment elective, particularly for levodopa-safe Parkinson's symptoms. Cannabinoids compounds like delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the most abundant chemicals present. Whereas THC is psychotropic chemical that tends to cause individuals to feel "high," while CBD is no psychotropic chemical. Nonetheless, other than cannabis, plant cannabinoids are also produced by the mammalian body, called endocannabinoids. Endocannabinoids are neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins expressed throughout the central nervous system, including the brain and peripheral nervous system. So, these endocannabinoid receptors can be of two types cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R), which are G-protein coupled receptors. The first receptor, CB1R receptors are particularly abundant in the hippocampus, frontal cortex, basal ganglia, hypothalamus and cerebellum, spinal cord and peripheral nervous system. They can also be found in inhibitory GABA-ergic neurons and excitatory glutamatergic neurons. Whereas CB2R receptor is most abundantly found on cells of the immune system hematopoietic cells and glial cells. CB2R receptor is mainly found in the periphery under normal healthy conditions, but in the case due to disease or injury, this regulation occurs within the brain, and CB2R is therefore expressed in the brain in disease or injured person.

Keywords: Levodopa, Cannabidiol (CBD), Cannabinoid, Cannabis, Delta-9-tetrahydrocannabinol (THC), Parkinson’s disease, Tremor

INTRODUCTION: The most common neuro-degenerative disorder can be said as Parkinson’s disease (PD). PD is the gradual loss of dopaminergic neurons that destroy the basal ganglia, which is an important part of the brain for coordinated movement. Patients with PD experience motor symptoms, including bra-dykinesia (slowness and poverty of movement), resting tremor, muscular rigidity, and gait (impairment of postural balance).

Other than motor symptom, nonmotor symptoms can also appear which include excessive sweating, depression or, in late stages dementia. These changes are commonly cause by a loss of the pigmented dopaminergic neurons of the substantia nigra (SN) which innervate the striatum. In recent year, investigation have shown the considerable progress in understanding the pathophysiology of PD.

Several factors causing neuronal damage are probably involved ¹, their common denominator seems to be an oxidative stress. So, this oxidative stress which causes imbalance between the formation of cellular oxidants and the antioxidative processes in SN neurons, which lead to excessive formation of hydrogen peroxide and oxygen-derived free radicals that can seriously damage the neurons and which in turn lead to neuronal cell death ². Marijuana refers to the dried flowers, stems, seeds, and leaves derived from the cannabis sativa plant various Phytocannabinoids ³. So, phytocannabinoids are used to differentiate the plant-derived cannabinoids from the synthetic cannabinoids and the structurally different endogenous cannabinoids (endocannabinoids). The Cannabis sativa plant, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), has various potency effects on diseases like cancer, glaucoma, and multiple sclerosis. There are several evidences demonstrate that dopamine depletion causes a dramatic rearrangement in the striatal endocannabinoid system, endocannabinoid (ECB) plays a vital role in neuronal regulation and immune function within the central nervous system (CNS) and is altered in several movement disorders; this occurrence can be seen in both rodent and primate models of PD, as well as in PD patients. In fact, close interactions exist between endocannabinoids and the dopaminergic system in the regulation of synaptic function and regulation of motor behaviour, through specific G protein-coupled cannabinoid receptors (CB1 and CB2) in the basal ganglia ⁴.

Cannabinoid receptors and endogenous cannabinoids isolation in the nervous system is proposed by Raphael Mechoulam ⁵ and his colleague, and their discovery that the endocannabinoid system is capable of modulating numerous physiological processes, such as pain, eating behaviour, memory, and mood, have paved the way for systematic research into the effects of cannabis on a variety of chronic diseases ⁶. Until that is March 10, 2017, cannabis flowers and their extracts can be prescribed on a narcotic drug prescription form without limitation to specific indications ⁷. The discovery of high concentrations of cannabinoid receptors in the basal ganglia can trigger an increasing interest in the therapeutic potential of cannabinoids for the treatment of diseases like Parkinson’s disease (PD) and other movement disorders. Hence, Public awareness of such a topic was raised by anecdotal reports of considerable improvement of PD symptoms after cannabis consumption that were shared via social networks and published in the general press.

1. Terminology of Cannabis: Marijuana, also known as cannabis sativa is an herbaceous plant that has versatile uses and effects. However, the leaves and resinous extracts of the plant can be consumed by eating, smoking, or even inhaling vapors. Moreover, cannabis hemp seeds can also be used for producing oil for cooking, lighting, and wood surface coatings. Until recently, the main interest in this plant is that it has a rich source of cannabinoids. These cannabinoids are chemical substances consumed largely for recreational and spiritual purposes and for their medicinal effects. The difference in the chemical structure of cannabinoids explains the difference in their psychoactive and therapeutic effects. The two cannabinoids of greatest interest today are cannabidiol (CBD) and (Delta)9- Tetrahydrocannabinol (∆9- or D9-trahy--drocannabinol; THC). CBD is one of the major non-psychoactive Phyto-cannabinoids which is present in cannabis such that nearly 40% of cannabis extracts are comprised of CBD and CBD is also a substance in cannabis that is thought to have potential medicinal applications ⁸ lack psycho-activity and not interfere with psychomotor learning or neuropsychological functions. Whereas THC, the other main active component in cannabis, is also responsible for the mood-altering effects, and unlike CBD, THC has potent adverse psychoactive effects, inducing anxiety and paranoia ⁹, the interesting prospect is the possibility that CBD may be capable of counteracting adverse psychoactive effects of THC in humans ¹⁰.

2. Current Problem Face with PD Medical Treatment: Direct-acting dopamine receptor agonists have been a major focus of PD drug development over the past decades. In recent years, their potential to provide more continuous dopaminergic receptor stimulation than levodopa has been the subject of both preclinical and clinical research. Dopamine agonists were investigated for a better substitution of dopaminergic in PD than levodopa due to having a longer half-life and because some are amenable to continuous parenteral drug delivery through different routes. In fact, most dopamine agonists studied in clinical trials have shown consistent efficacy in reducing motor response ¹¹. Nonetheless, data from comparative studies between different agonists and greater efficacy of agonists with longer half-lives, or continuous transdermal delivery on motor fluctuations, has not been established. Henceforth, studies in parkinsonian in primates have shown that treatment with short-acting dopamine agonists, but not with longer-acting ones, induces dyskinesias, supporting the hypothesis of pulsatile dopamine receptor stimulation as a critical factor for the development of dyskinesias ¹². At a clinical level, there is large evidence to support that continuous dopaminergic drug delivery can revert pre-existing levodopa-induced dyskinesias. This was observed with intraduodenal infusions of levodopa itself, which were found to smooth out motor oscillations and reduce dyskinesia severity despite more or less unchanged total daily dose ¹³. In similar observations were made in studies of continuous s.c. Infusions of the dopamine agonists, lisuride or apomorphine, in which concomitant levodopa was usually reduced while the agonist was infused at rates to ensure maximal dystonic posturing reduction ¹⁴.

In addition, clinical studies have shown that dyskinetic responses to single-dose levodopa challenges were markedly reduced following several months of continuous s.c. apomorphine infusions ¹⁵.

So, due to these several problems with the long-term use of levodopa causing dyskinesia, replacement therapy is being investigated for better treatment of PD.

3. Cannabinoid Receptors Relations to CNS Dysfunction: ECB act as a retrograde messenger on presynaptic cannabinoid receptors, albeit additional molecular targets might be involved. Cannabinoid receptors can be divided into two major subtypes, which are CB1R and CB2R ¹⁶ Fig. 1. This CB2R is mostly found in the immune system, whereas CB1R is highly expressed and localized to several area regions of the brain, with a reported expression in neurons, astrocytes, oligodendrocytes, and neural stem cells ¹⁷.

FIG. 1: SCHEMATIC REPRESENTATION EXPLAINING THE INTERACTIONS BETWEEN CANNABINOID SYSTEM AND DOPAMINERGIC TRANSMISSION AT BASAL GANGLIA LEVEL

There is noticeably high expression of CB1R in the cerebellum, particularly on its input into Purkinje cells from the inhibitory basket and stellate interneurons and excitatory climbing fibers, which arise from granule cells, thus indicating the crucial role of CB1R in cerebellar function. In addition, it also shows that CB1R knockout mice, as well as chronic marijuana users or animals administered CB1R agonists, have a clear impairment of eyeblink conditioning, an epitome of cerebellar cortex function ¹⁸. 2-Arachidonoylglycerol (2-AG) and Arachidonoylethanolamide (AEA), two arachidonic acid derivatives, are the major component of endocannabinoids in the brain, cerebellum. At the same time, CB1R is predominantly activated by 2-AG. Increase in the concentration of postsynaptic Ca2+ either by entry through voltage-gated Ca2+ channels or by the activation of type 1 metabotropic glutamate receptors which causes the release of 2-AG synthesized from diacylglycerol, which is nothing but the reaction catalyzed by diacylglycerol lipase-alpha in the Purkinje cells, with the overall effect of activation of presynaptic CB1R ¹⁹. Moreover, some studies reported the high density of CB1Rs in the striatum and AEA presence throughout the basal ganglia, particularly in the globus pallidus and substantia nigra. Crosstalk between the dopaminergic transmission and ECB signaling in the striatum nigra can be considered great evidence that shows CB1R activation by ECB retrograde signaling and has a great potential to decrease glutamate release in dopaminergic D2 receptor-dependent manner ²⁰.

ECB signaling is bidirectionally linked to dopaminergic signaling within the basal ganglia. CB1, D2, and D1 dopamine receptors are localized in the striatum. In animal models, CB1 and D2 dopamine receptors have a common pool of G proteins, which link their signal transduction mechanisms ²¹. In addition to this, D2 receptor stimulation resulted in the release of ECBs in the striatum. Although, stimulation of CB1 receptors completely inhibited the D1-dopamine receptor stimulating the activation of adenylyl cyclase and decreased GABA release from striatal afferents of dopaminergic neurons of the substantia nigra, which resulted in an increased firing of these cells ²². Another receptor is involved in the control of movement; it is transient receptor potential vanilloid type 1 (TRPV1); these are expressed in sensory neurons and basal ganglia circuitry of dopaminergic neurons. TRPV1 receptors are molecular integrators of nociceptive stimuli activated by Endo vanilloids ²³. TRPV1 also interacts with ECB; particular anandamide is one of the major endogenous activators of TRPV1 ²⁴. Recent studies have shown that motor behaviour can be suppressed by activating vanilloid receptors 25, hinting that TRPV1 receptors can play a vital role in controlling motor function.

4. Therapeutic features of Cannabis: Cannabis and cannabinoid have an excellent therapeutic potential related to the effects of THC, CBD, and other cannabinoid compounds. Nonetheless, the high effect of THC in cannabis and cannabinoid may limit clinical use; due to this reason, the study on the therapeutic potential of THC alone is more limited. CNS effects of THC include disruption of psychomotor behavior, anti-nociceptive, stimulation of appetite, short-term memory impairment, and antiemetic effects ²⁶. Other known risk factors involved with long-term use of cannabis include diminished IQ and brain mass, lower cognitive function, low motivation, and poor judgment. It could hasten, worsen, unmask psychosis and chronic bronchitis ²⁷. Some evidence shows cardiovascular effects of THC shown in the chronic users of cannabis. Moreover, it was found to increase the risks of stroke and heart attack.

So, from this, we can indicate that THC extracted from the Phyto cannabinoids has shown to activate the platelets through CB1 and CB2 receptors, leading to increased GPllb-llla expression and activation of factor Vll, that have a potent thrombogenic protein resulting in stroke and heart attack ²⁸. Therefore, most research studies emphasize the therapeutic potentials of CBD due to the non-psychotropic chemical of CBD and the combination of THC with CBD. There are clinical research studies of CBD in a variety of neuropsychiatric disorders. Including Parkinson’s disease, autistic spectrum disorder 29, anxiety disorder, schizophrenia, neuropathic pain, Huntington disease, Alzheimer's disease, hypoxic ischemic injury, and epilepsy ³⁰.

5. Role of Endocannabinoid: The products extracted from the cannabis plant consist of a large number of Phytocannabinoids, a term used to differentiate cannabinoids derived from the plant, from those found in the body (i.e., endocannabinoids) or those chemically synthesized (i.e., endocannabinoids or exo-CBs), of about 100 phyto-CBs contained in the plant there are two significant ones, namely cannabidiol (CBD) and delta-9-Tetrahydrocannabinol (∆9-THC). Cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (Δ9-THC, THC) are the major constituents of marijuana ³¹ among the cannabinoids. Δ9-THC is a psychoactive agent with analgesic and muscle relaxant properties, whereas CBD is a non-psychoactive compound that is shown to have hypnotic, anxiolytic, antipsychotic, antioxidant, and neuroprotective effects ³², THC is a partial agonist at the cannabinoid receptor 1 (CB1) and receptor 2 (CB2). CBD, unlike those Δ9-THC has an antagonistic or inverse agonistic property at the CB1 receptor; it also appears to regulate Δ9-THC-associated side effects like anxiety, tachycardia, and hunger. By inhibiting their inactivation, CBD also appears to have the same potentiation effect as endocannabinoids, hence alleviating psychotic symptoms ³³. Endocannabinoid (ECB) plays a vital role in neuronal regulation and immune function within the central nervous system (CNS) and is altered in several movement disorders. The cannabinoid receptors are expressed on multiple neuronal populated areas and microglial cells, hinting that activation of these different receptor populations can modulate basal ganglia function in one of various movements disorders ³⁴.

Cannabinoid 1 (CB1) receptor is the most common cannabinoid receptor that is found throughout the CNS, with high levels of expression in the basal ganglia ³⁵. This CB1 receptor is found on the presynaptic cortical-striatal glutamatergic nerve terminals and decreases the influx of calcium, thereby decreasing glutamate release from the nerve terminal ³⁶. Medium spiny GABAergic neurons within the striatum express CB1 receptors on dendrites and on their presynaptic terminals, which project to the internal and external segments of the globus pallidus and substantia nigra pars reticulata, and are involved in inhibition of GABA release from presynaptic terminals ³⁷ CB1 receptors are also found on striatal interneurons and on the glutamatergic neurons projecting from the subthalamic nucleus to the internal segment of the globus pallidus ³⁸. The cannabinoid 2 (CB2) receptors are primarily found on the CNS of glial cells and a subset of a neuronal populated area in the cerebellum and brainstem ³⁹.

Moreover, CB2 receptors are widely expressed outside the CNS, especially on immune cells. The expression of the CB2 receptor has increased on activation of microglial cells. Through the binding of these receptors, the endocannabinoids also decrease in activation of proinflammatory pathways and cytokine production. These CB1 and CB2 receptors are G protein-linked receptors coupled to intracellular signaling pathways, which can modulate several downstream signaling cascades that alter protein function, gene expression and proinflammatory mediators and release of neurotransmitter ⁴⁰.       

6. Cannabis as Neuroprotection in PD: In early years, in animals’ studies demonstrated an effect of cannabinoids on the catecholaminergic and dopaminergic systems ⁴¹. So, a compound like Cannabinoid receptor 1 (CB-1R) and the endocannabinoid ligands anandamide and 2-ara-chidonylglycerol (2-AG) occur in high concentrations in the dopaminergic system, including the striatum, where they modulate dopaminergic transmission as a retrograde feedback system on presynaptic glutamatergic and GABAergic nerve endings.

In the late 1970s, an in-vitro study shows conflicting evidence, demonstrating an increase 42 and a dose-dependent decrease in dopamine synthesis and release. In contrast, in-vivo studies demonstrate an increase in dopamine release in the prefrontal cortex, striatum, and nucleus acumens. Hence, an increased firing rate of dopaminergic neurons after acute THC exposure can be assumed, resulting in augmented dopamine synthesis and release. Surprisingly, both acute and chronic THC exposure indicates a result in different effects on neuronal firing rate, transmitter synthesis, transmitter release, and reuptake within the dopaminergic system ⁴³. Endocannabinoid system (ECS) activity increase has been detected in a PD animal model and human tissue analyses from PD patients; this also includes upregulation of cannabinoid receptors ⁴⁴, an accumulation of cannabinoid receptor agonists, and even reduction in their degradation⁴⁵. This ECS adaptation can be reversed by chronic levodopa substitution in an animal model ⁴⁶.

Regarding the effect of CB-1R on motor function, experimental studies have shown heterogeneous and partially conflicting results. CB-1R direct activation can reduce dopamine release and show an increase in bradykinesia in MPTP (1-methyl – 4 – phenyl - 1, 2, 3, 6 -tetrahydropyridine) induced PD in animals model ⁴⁷. Improvement of motor impairment with cannabinoid receptor agonists can be seen in another report, possibly due to receptor-independent mechanism of action ⁴⁸. Moreover, alleviation of levodopa-induced dyskinesia has been reported for cannabinoid receptor agonists and antagonists ⁴⁹. Furthermore, ECS activation may confer neuroprotective such as direct receptor-independent mechanisms or activation of anti-inflammatory cascades in glial cells via cannabinoid receptor 2 (CB-2R) ⁵⁰ and anti-glutamatergic.

7. Cannabinoid System Activity Changes in PD: Recently, several studies show an important role of the endocannabinoid system in PD. Endocannabinoid system compounds are highly expressed in the neural circuit of basal ganglia, which is part of a complex neuronal system. So, this neuronal system coordinates activities from different cortical regions that directly or indirectly participate in controlling movement. The ECB's system in the basal ganglia bidirectionally interacts with dopaminergic, GABAergic, and glutamatergic signaling systems ⁵¹. These endocannabinoids play an important role in controlling transmission at synapses between cortical and striatal neurons, inducing a particular form of synaptic plasticity and modulating basal ganglia activity and motor functions ⁵².

PD associated progressive loss of dopaminergic neurons leads to lowering the striatal levels of dopamine. So, these low levels of dopamine result in the alteration of the equilibrium between the direct and the indirect basal ganglia pathways and ECB signaling ⁵³. The cannabinoid signaling system mentioned above shows a biphasic pattern of changes during the progression of PD ⁵⁴. In early and presymptomatic PD stages, characterized by a neuronal malfunction with little evidence of neuronal death, are associated with desensitization or downregulation of CB1R and aggravation of various cytotoxic effects such as oxidative stress excitotoxicity and glial activation ⁵⁵.

Nonetheless, the intermediate and advanced stages of PD are characterized by a deep nigral degeneration and the manifestation of major Parkinsonian symptoms associated with up regulatory responses of CB1R and the endocannabinoid ligands. Hence, this could help explain the potential of CB1Rligands in alleviating common symptoms of PD. In the brain area, CB1R is expressed by GABAergic neurons that stimulate globus pallidus and substantia nigra's external and internal segments. CB1R is also present in the various region like the corticostriatal glutamatergic terminals, in the excitatory projections from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra ⁵⁶. In the striatum, CB1R has expressed in parvalbumin immune-reactive interneurons, nitric oxide synthase-positive neurons and cholinergic interneurons ⁵⁷. Animal models of PD depicted an increase in the density of CB1R, levels of endogenous ligands, and even the CB1R, which binds to the basal ganglia ⁵⁸. Endogenous cannabinoids activate CB1R on presynaptic axons, which lead to reduced neurotransmitter and glutamate release, working as retrograde synaptic messengers released from postsynaptic neurons. Likewise, activation of CB1R inhibits both glutamate release from substantia nigra afferents and GABA release from striatal afferents. Simultaneously, presynaptic activation of CB1R in the external segments of the globus pallidus can lead to an increase in GABA levels by decreasing GABA reuptake from striatal carrying toward to the nucleus and reducing the GABA release from striatal toward the substantia nigra. In regards to this evidence, it is thought that ECB controls the function of the basal ganglia neuronal system. The presence of ECB systems in different neural structures and their interaction with dopaminergic, glutamatergic and GAB aergic neurotransmitter signaling systems make the components of ECB system an ideal target for a novel non-dopaminergic treatment of PD.

CONCLUSION: Recent studies show that cannabis and its compounds could serve a spromising therapeutic agent in the treatment of neurodegenerative and movement disorders, including Parkinson’s disease. So, we have searched for any scientific evidence that indicates the potential use of cannabis and its related compounds for PD treatment. The current treatment of PD only provide relief of motor symptoms and are associated with adverse effects such as dyskinesia. Moreover, they do not slow the progression of the disease. Therefore, there is an urgent need for a safer drug that can treat both motor and nonmotor symptoms of PD and drugs that slow the progression of the disease. These actions of cannabinoids are mostly through G protein-coupled cannabinoid CB1 (CB1R) and G protein-coupled cannabinoid CB2 (CB2R) activation. So, we can see that cannabinoid receptors and endocannabinoids are most abundant in the brain areas involved in the management of motor function and have a significant role in modulating many motor functions. Nonetheless, the exact molecular mechanisms of cannabinoid signaling in the pathogenesis of motor-related diseases have not been fully understood, and there are still various significant gaps in our understandings of their influence on motor pathways. Still, medical cannabis appears to have a huge benefit among some of the patients enduring tremor-associated diseases. Therefore, there is a need to improve and develop novel therapeutic strategies using cannabinoid-based medicines with fewer side effects. SO, in this review, we can reasonably conclude that cannabinoids have a potential effect for the management of Parkinson’s symptoms and other neuro diseases and some patients with motor-related diseases.

ACKNOWLEDGEMENT: The authors would like to thank The Oxford College of Pharmacy, Bangalore, for the support and help provided in the completion of the

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Chhakchhuak DZ, Tabassum GSS and Raj A: Review on activity of cannabis treatment on Parkinson’s disease. Int J Pharm Sci & Res 2022; 13(6): 2221-29. doi: 10.13040/IJPSR.0975-8232.13(6).2221-29.

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