Parkinson’s disease and cannabinoids
December 3, 2021
Cannabinoids used in Pain Management
January 21, 2022Scientific information for healthcare professionals
Author : Dr.Elmo Resende, Ph.D | Director of R&D - Piauhy Labs
Parkinson's disease treated with cannabinoids
Now you’re already familiarized with Parkinson’s disease and its common symptoms, and knowing possible alternative treatments used with cannabis plant, in our next article we explore deeper this topic. Endocannabinoid System (ECS) can be activated by cannabinoid chemical compounds, meaning that it can stimulate biological and pharmacological properties of terpenoids – such as antimicrobial, antifungal, antiviral or antiparasitic. Our aim in this article is to explore and analyze benefits of Cannabis plant compounds and its connection to prevent, decrease and even repairing neurodegeneration, as Parkinson’s disease.
Parkinson’s disease treated with cannabinoids | Benefits of plant’s compounds
The phytocompounds, chemicals present in the Cannabis sativa plant, act as inhibitors for the presynaptic neuronal protein α-synuclein aggregation, as activation of the c-Ju N-terminal kinase (JNK) protein and the production of monoamine oxidase, and are agonists for dopaminergic neurons in PD. Considering the socioeconomic burden and undesirable side effects of synthetic drugs, natural remedies are a promising avenue for the treatment of PD.
Terpenes are one of the most extensively naturally occurring compounds, with the greatest molecular variation between secondary metabolites occurring in nature or naturally. Terpenes are mainly used commercially as flavors, fragrances, nutraceutical compounds, pharmaceuticals as therapeutic agents and industrial chemicals.
Terpenes are mainly categorized as mono-, sesqui-, di-, ses-, tri-, and tetraterpenes, which are classified as dependent on the number of isoprenoid units present in them.
The biological and pharmacological properties of terpenoids include cancer and chemopreventive effects, antihyperglycemic activity, antimicrobial, antifungal, antiviral, anti-inflammatory and antiparasitic activity.
Parkinson’s disease treated with cannabinoids | Benefits of CBD receptors in human body
CBD receptors are spread across many areas of the brain as well as other parts of the body, including the gastrointestinal tract and the immune system. In the brain, studies reveal that CBD acts on the medial prefrontal cortex (mPFC), amygdala and hippocampus, which are areas directly related to the reward system. Therefore, it is reasonable to explore how CBD might be a potential treatment target for addiction disorders.
The CB1 receptors are also distributed in sleep-related areas, including the basal and pedunculopontine forebrain and the laterodorsal nucleus, and are expressed in cholinergic neurons. The activation of these receptors by CBD could favor the release of acetylcholine and, consequently, cause symptom improvement through a mechanism similar to that proposed for anticholinesterase drugs.
Cannabinoids are highly active anti-inflammatory agents, an effect that has normally been associated with the activation of the cannabinoid receptor type 2 (CB2), whose benefits have been extensively investigated in experimental models of PD. The anti-inflammatory properties of cannabinoids have recently been reinforced with the observation that different pCBs and their derivatives, as well as the eCBs anandamide and 2-arachidonoylglycerol, and related signaling lipids such as palmitoylethanolamide and oleethanolamide, can also bind and activate certain specific types of receptors of the family of peroxisome proliferators activated receptors (PPAR).
A series of quinone derivatives of pCB Cannabigerol (CBG), which behave as activators of PPAR-γ showing negligible affinity at CB1/CB2 receptors, unlike their phytocannabinoid (CBG) model, was recently designed, synthesized and characterized. One of them, the aminoquinone derivative of CBG, called VCE-003.2, was recently investigated in murine models of Huntington's disease, confirming its neuroprotective profile, which is exerted by the activation of PPAR-γ and its ability to cross the blood-brain barrier after systemic administration.
In a more recent study, these anti-inflammatory and neuroprotective properties of VCE-003.2 were investigated in mice injured with lipopolysaccharide (LPS), the experimental model of Parkinson's disease that best reproduces inflammation as a pathogenic event in this disease.
One of the relevant terpene’s compounds is the called α-pinene, main ingredient in essential oils from various plants, including Cannabis sativa, and has been shown to inhibit the activity of acetylcholinesterase. It also has antidepressant, anticonvulsant, antioxidant, antispasmodic, antibacterial, anti-inflammatory and antitumor properties.
Like β-pinene compound, α-pinene is best known for its anti-inflammatory benefits. They are useful for conditions such as arthritis, Crohn's disease and multiple sclerosis. With respect to other conditions, by working synergistically with THC, α-pinene acts as a bronchodilator, opening the airways at low levels of exposure to help with conditions such as asthma.
Working with CBD and CBN, it has a broad spectrum of antibiotic properties, which work against diseases such as methicillin-resistant Staphylococcus aureus (MRSA). The α -pinene can also counteract the unwanted effects of THC, such as anxiety and short-term memory. It works by inhibiting the activity of acetylcholinesterase in the brain, which helps to retain memories more efficiently. Other benefits include euphoria, increased alertness, a reduction in oil production in oily skin and, most interestingly, it has anti-cancer properties. Some studies suggest that α-pinene can stop tumor growth and complement chemotherapy treatments.
Studies show that α-pinene's antioxidant properties play an important role in its protective effects, suggesting that it is used as an adjunctive treatment in patients with PD.
Several studies have analyzed the neuroprotective effect of α-pinene. Since many drugs on the market for the treatment of neurodegenerative diseases (e.g., Alzheimer's disease, epilepsy, PD) cause serious side effects, there is a focus on new agents. Moreover, α-pinene has the potential to reduce symptoms of neurodegenerative diseases.
Some studies show that molecular genetics and biochemical evidences supports the hypothesis that α-synuclein oligomers play a central role in the pathogenesis of PD and its related disorders. Several intra- and extracellular mechanisms by which such prefibrillary α-synuclein species exert detrimental effects have been identified.
Genetic studies describe mutations in α-synuclein, PINK1, DJ-1 (PARK7), ubiquitin genes such as ubiquitin-C-hydrolase, and population-specific gene mutations such as the glucocerebrosidase gene present in Jews Ashkenazi, are directly related to the onset of PD. Evidence suggests that mutations in molecular signaling, such as leucine-rich repeat kinase 2 (LRRK2) and Miro GTPases, play a vital role in the onset and progression of this disease.
Therefore, this brings back to the idea that, simultaneously, knowledge of the molecular mechanism is essential in the development of therapeutics for effective prevention or cessation of neurodegeneration as well as the repair process.
A recent study related with Tg4-42 transgenic mice expressing human Aβ4-42 treated with Δ9 -THC showed reduced neuronal loss when compared to controls. In addition, a study used an N2a variant of β amyloid precursor cells (AβPP) treated with THC and concluded showing a neuroprotective effect exerted on the cells, as THC could significantly decrease the levels of Aβ in the cell. It is also believed that the response is time dependent and that repeated treatments gradually decrease Aβ synthesis.
Parkinson’s treated with cannabinoids | Endocannabinoid system related to neurodegenerative diseases
The relationship between the ECS and neurodegenerative diseases has been intensively studied from the perspective of neuroinflammation. However, the effects of ECS on microglia, on neuroinflammation, are not well established yet and the data associated with these facts are limited.
Several recent studies have discussed the association between the endocannabinoid system and the microglial phenotype in neuropathology. In fact, current knowledge suggests that microglia in a normal, healthy brain maintain homeostasis with M0-type morphology. Microglial activation and polarization due to an injury or related stimulus induces the secretion of proinflammatory cytokines for neuroinflammation with classical M1 type morphology.
PD is known to have a multifactorial etiology; however, the precise involvement of genetics, environment and behavioral factors must be elucidated. It is well evidenced that research studies so far have focused primarily on clinical and epidemiological studies rather than molecular-based investigations. Molecular approaches show a high demand and importance to determine the genetics and other aspects of the endocannabinoid system involved in the onset of Parkinson's disease for the development of therapeutic drugs aimed at preventing, stopping, and even repairing neurodegeneration.
Parkinson’s disease treated with cannabinoids | Piauhy Labs Mission
Piauhy Labs intends to obtain a Certification of Compliance with Good Laboratory Practices, in accordance with the principles of the OECD, for the pharmaceutical area, so that the results obtained from its research are properly used for the granting of licenses or for the registration of pharmaceutical products, including medicines for human use and similar products.
As a result of the intended research processes, Piauhy Labs to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines that improve the quality of life of patients suffering from various diseases, including Parkinson's disease.
References
Allenspach, M. and Steuer, C. α-Pinene: A never-ending story. Phytochemistry, volume 190, October, 112857, 2021.
Bassi, M. S.; Sancesario, A.; Morace, R.; Centonze, D. and Iezzi, E. Cannabinoids in Parkinson’s Disease. Cannabis and Cannabinoid Research, Volume 2.1, 2017.
Burgaz, S.; García, C.; Gómez-Cañas, M.; Muñoz, E. and Fernández-Ruiz, J. Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease. Molecules 24, 2702, 2019.
Chagas, M. H. N.; Eckeli, A. L.; Zuardi, A., et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J. Clin. Pharm. Ther. Oct;39(5):564-6, 2014.
Chagas, M. H. N.; Zuardi, A. W.; Tumas, V. et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J. Psychopharmacol., Nov, 28 (11):1088-98, 2014.
Ferreira-Junior, N. C.; Campos, A. C.; Guimarães, F. S., Del-Bel, E.; Zimmermann, P. M. R.; Brum Junior, L., et al. Biological bases for a possible effect of cannabidiol in Parkinson’s disease. Braz. J. Psychiatr. 42 (2), Mar-Apr, 2020.
Goudarzi, S. and Rafieirad, M. Evaluating the effect of α-pinene on motor activity, avoidance memory and lipid peroxidation in animal model of Parkinson disease in adult male rats. Research Journal of Pharmacognosy (RJP) 4(2), 53-63, 2017.
Hickman, S.; Izzy, S.; Sen, P.; Morsett, L. and El Khoury, J. Microglia in neurodegeneration. Nature Neuroscience 21(10), 1359–1369, 2018.
Ingelsson, M. Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front. Neurosci. 10:408, 2016.
Kaura, K.; Khuranaa, N. and Sharmaa, N. Phytochemicals as Future Drugs for Parkinson´s Disease: A Review. Plant Archives 21, Supplement 1, 2338-2349, 2021.
Kessler, F. H.; von Diemen, L.; Ornell, F. and Sordi, A. O. Cannabidiol and mental health: possibilities, uncertainties, and controversies for addiction treatment. Braz. J. Psychiatry May 17, 2021.
Pradeep Kumar, P.; Mahato, D. K.; Kamle, M.; Borah, R.; Sharma, B.; Pandhi, S.; Tripathi, V.; Yadav, H. S.; Devi, S.; Patil, U.; Xiao; J. and Mishra, A. K. Pharmacological properties, therapeutic potential, and legal status of Cannabis sativa L.: An overview. Phytother. Res. Jul 8, 2021.
Sexton, M. Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence. The Journal of Alternative and Complementary Medicine, Volume 26, Number 6, 444–448, 2020.
Stasiłowicz, A.; Tomala, A.; Podolak, I. and Cielecka-Piontek, J. Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment. Int. J. Mol. Sci. 22, 778, 2021.
Parkinson's disease treated with cannabinoids
Now you’re already familiarized with Parkinson’s disease and its common symptoms, and knowing possible alternative treatments used with cannabis plant, in our next article we explore deeper this topic. Endocannabinoid System (ECS) can be activated by cannabinoid chemical compounds, meaning that it can stimulate biological and pharmacological properties of terpenoids – such as antimicrobial, antifungal, antiviral or antiparasitic. Our aim in this article is to explore and analyze benefits of Cannabis plant compounds and its connection to prevent, decrease and even repairing neurodegeneration, as Parkinson’s disease.
Parkinson’s disease treated with cannabinoids | Benefits of plant’s compounds
The phytocompounds, chemicals present in the Cannabis sativa plant, act as inhibitors for the presynaptic neuronal protein α-synuclein aggregation, as activation of the c-Ju N-terminal kinase (JNK) protein and the production of monoamine oxidase, and are agonists for dopaminergic neurons in PD. Considering the socioeconomic burden and undesirable side effects of synthetic drugs, natural remedies are a promising avenue for the treatment of PD.
Terpenes are one of the most extensively naturally occurring compounds, with the greatest molecular variation between secondary metabolites occurring in nature or naturally. Terpenes are mainly used commercially as flavors, fragrances, nutraceutical compounds, pharmaceuticals as therapeutic agents and industrial chemicals.
Terpenes are mainly categorized as mono-, sesqui-, di-, ses-, tri-, and tetraterpenes, which are classified as dependent on the number of isoprenoid units present in them.
The biological and pharmacological properties of terpenoids include cancer and chemopreventive effects, antihyperglycemic activity, antimicrobial, antifungal, antiviral, anti-inflammatory and antiparasitic activity.
Parkinson’s disease treated with cannabinoids | Benefits of CBD receptors in human body
CBD receptors are spread across many areas of the brain as well as other parts of the body, including the gastrointestinal tract and the immune system. In the brain, studies reveal that CBD acts on the medial prefrontal cortex (mPFC), amygdala and hippocampus, which are areas directly related to the reward system. Therefore, it is reasonable to explore how CBD might be a potential treatment target for addiction disorders.
The CB1 receptors are also distributed in sleep-related areas, including the basal and pedunculopontine forebrain and the laterodorsal nucleus, and are expressed in cholinergic neurons. The activation of these receptors by CBD could favor the release of acetylcholine and, consequently, cause symptom improvement through a mechanism similar to that proposed for anticholinesterase drugs.
Cannabinoids are highly active anti-inflammatory agents, an effect that has normally been associated with the activation of the cannabinoid receptor type 2 (CB2), whose benefits have been extensively investigated in experimental models of PD. The anti-inflammatory properties of cannabinoids have recently been reinforced with the observation that different pCBs and their derivatives, as well as the eCBs anandamide and 2-arachidonoylglycerol, and related signaling lipids such as palmitoylethanolamide and oleethanolamide, can also bind and activate certain specific types of receptors of the family of peroxisome proliferators activated receptors (PPAR).
A series of quinone derivatives of pCB Cannabigerol (CBG), which behave as activators of PPAR-γ showing negligible affinity at CB1/CB2 receptors, unlike their phytocannabinoid (CBG) model, was recently designed, synthesized and characterized. One of them, the aminoquinone derivative of CBG, called VCE-003.2, was recently investigated in murine models of Huntington's disease, confirming its neuroprotective profile, which is exerted by the activation of PPAR-γ and its ability to cross the blood-brain barrier after systemic administration.
In a more recent study, these anti-inflammatory and neuroprotective properties of VCE-003.2 were investigated in mice injured with lipopolysaccharide (LPS), the experimental model of Parkinson's disease that best reproduces inflammation as a pathogenic event in this disease.
One of the relevant terpene’s compounds is the called α-pinene, main ingredient in essential oils from various plants, including Cannabis sativa, and has been shown to inhibit the activity of acetylcholinesterase. It also has antidepressant, anticonvulsant, antioxidant, antispasmodic, antibacterial, anti-inflammatory and antitumor properties.
Like β-pinene compound, α-pinene is best known for its anti-inflammatory benefits. They are useful for conditions such as arthritis, Crohn's disease and multiple sclerosis. With respect to other conditions, by working synergistically with THC, α-pinene acts as a bronchodilator, opening the airways at low levels of exposure to help with conditions such as asthma.
Working with CBD and CBN, it has a broad spectrum of antibiotic properties, which work against diseases such as methicillin-resistant Staphylococcus aureus (MRSA). The α -pinene can also counteract the unwanted effects of THC, such as anxiety and short-term memory. It works by inhibiting the activity of acetylcholinesterase in the brain, which helps to retain memories more efficiently. Other benefits include euphoria, increased alertness, a reduction in oil production in oily skin and, most interestingly, it has anti-cancer properties. Some studies suggest that α-pinene can stop tumor growth and complement chemotherapy treatments.
Studies show that α-pinene's antioxidant properties play an important role in its protective effects, suggesting that it is used as an adjunctive treatment in patients with PD.
Several studies have analyzed the neuroprotective effect of α-pinene. Since many drugs on the market for the treatment of neurodegenerative diseases (e.g., Alzheimer's disease, epilepsy, PD) cause serious side effects, there is a focus on new agents. Moreover, α-pinene has the potential to reduce symptoms of neurodegenerative diseases.
Some studies show that molecular genetics and biochemical evidences supports the hypothesis that α-synuclein oligomers play a central role in the pathogenesis of PD and its related disorders. Several intra- and extracellular mechanisms by which such prefibrillary α-synuclein species exert detrimental effects have been identified.
Genetic studies describe mutations in α-synuclein, PINK1, DJ-1 (PARK7), ubiquitin genes such as ubiquitin-C-hydrolase, and population-specific gene mutations such as the glucocerebrosidase gene present in Jews Ashkenazi, are directly related to the onset of PD. Evidence suggests that mutations in molecular signaling, such as leucine-rich repeat kinase 2 (LRRK2) and Miro GTPases, play a vital role in the onset and progression of this disease.
Therefore, this brings back to the idea that, simultaneously, knowledge of the molecular mechanism is essential in the development of therapeutics for effective prevention or cessation of neurodegeneration as well as the repair process.
A recent study related with Tg4-42 transgenic mice expressing human Aβ4-42 treated with Δ9 -THC showed reduced neuronal loss when compared to controls. In addition, a study used an N2a variant of β amyloid precursor cells (AβPP) treated with THC and concluded showing a neuroprotective effect exerted on the cells, as THC could significantly decrease the levels of Aβ in the cell. It is also believed that the response is time dependent and that repeated treatments gradually decrease Aβ synthesis.
Parkinson’s treated with cannabinoids | Endocannabinoid system related to neurodegenerative diseases
The relationship between the ECS and neurodegenerative diseases has been intensively studied from the perspective of neuroinflammation. However, the effects of ECS on microglia, on neuroinflammation, are not well established yet and the data associated with these facts are limited.
Several recent studies have discussed the association between the endocannabinoid system and the microglial phenotype in neuropathology. In fact, current knowledge suggests that microglia in a normal, healthy brain maintain homeostasis with M0-type morphology. Microglial activation and polarization due to an injury or related stimulus induces the secretion of proinflammatory cytokines for neuroinflammation with classical M1 type morphology.
PD is known to have a multifactorial etiology; however, the precise involvement of genetics, environment and behavioral factors must be elucidated. It is well evidenced that research studies so far have focused primarily on clinical and epidemiological studies rather than molecular-based investigations. Molecular approaches show a high demand and importance to determine the genetics and other aspects of the endocannabinoid system involved in the onset of Parkinson's disease for the development of therapeutic drugs aimed at preventing, stopping, and even repairing neurodegeneration.
Parkinson’s disease treated with cannabinoids | Piauhy Labs Mission
Piauhy Labs intends to obtain a Certification of Compliance with Good Laboratory Practices, in accordance with the principles of the OECD, for the pharmaceutical area, so that the results obtained from its research are properly used for the granting of licenses or for the registration of pharmaceutical products, including medicines for human use and similar products.
As a result of the intended research processes, Piauhy Labs to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines that improve the quality of life of patients suffering from various diseases, including Parkinson's disease.
References
Allenspach, M. and Steuer, C. α-Pinene: A never-ending story. Phytochemistry, volume 190, October, 112857, 2021.
Bassi, M. S.; Sancesario, A.; Morace, R.; Centonze, D. and Iezzi, E. Cannabinoids in Parkinson’s Disease. Cannabis and Cannabinoid Research, Volume 2.1, 2017.
Burgaz, S.; García, C.; Gómez-Cañas, M.; Muñoz, E. and Fernández-Ruiz, J. Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease. Molecules 24, 2702, 2019.
Chagas, M. H. N.; Eckeli, A. L.; Zuardi, A., et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J. Clin. Pharm. Ther. Oct;39(5):564-6, 2014.
Chagas, M. H. N.; Zuardi, A. W.; Tumas, V. et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J. Psychopharmacol., Nov, 28 (11):1088-98, 2014.
Ferreira-Junior, N. C.; Campos, A. C.; Guimarães, F. S., Del-Bel, E.; Zimmermann, P. M. R.; Brum Junior, L., et al. Biological bases for a possible effect of cannabidiol in Parkinson’s disease. Braz. J. Psychiatr. 42 (2), Mar-Apr, 2020.
Goudarzi, S. and Rafieirad, M. Evaluating the effect of α-pinene on motor activity, avoidance memory and lipid peroxidation in animal model of Parkinson disease in adult male rats. Research Journal of Pharmacognosy (RJP) 4(2), 53-63, 2017.
Hickman, S.; Izzy, S.; Sen, P.; Morsett, L. and El Khoury, J. Microglia in neurodegeneration. Nature Neuroscience 21(10), 1359–1369, 2018.
Ingelsson, M. Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front. Neurosci. 10:408, 2016.
Kaura, K.; Khuranaa, N. and Sharmaa, N. Phytochemicals as Future Drugs for Parkinson´s Disease: A Review. Plant Archives 21, Supplement 1, 2338-2349, 2021.
Kessler, F. H.; von Diemen, L.; Ornell, F. and Sordi, A. O. Cannabidiol and mental health: possibilities, uncertainties, and controversies for addiction treatment. Braz. J. Psychiatry May 17, 2021.
Pradeep Kumar, P.; Mahato, D. K.; Kamle, M.; Borah, R.; Sharma, B.; Pandhi, S.; Tripathi, V.; Yadav, H. S.; Devi, S.; Patil, U.; Xiao; J. and Mishra, A. K. Pharmacological properties, therapeutic potential, and legal status of Cannabis sativa L.: An overview. Phytother. Res. Jul 8, 2021.
Sexton, M. Cannabis in the Time of Coronavirus Disease 2019: The Yin and Yang of the Endocannabinoid System in Immunocompetence. The Journal of Alternative and Complementary Medicine, Volume 26, Number 6, 444–448, 2020.
Stasiłowicz, A.; Tomala, A.; Podolak, I. and Cielecka-Piontek, J. Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment. Int. J. Mol. Sci. 22, 778, 2021.
