Category Archives: Parkinson’s Disease

Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels

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“Numerous studies have explored the role of cannabinoids in neurological conditions, chronic pain and neurodegenerative diseases. Restoring autophagy has been proposed as a potential target for the treatment of neurodegenerative diseases.

In our study, we used a neuroblastoma cell line that overexpresses wild-type α-synuclein to investigate the effects of cannabidiol on autophagy modulation and reduction in the level of cytosolic α-synuclein.

Our results demonstrated that cannabidiol enhances the accumulation of LC3-II- and GFP-LC3-positive vesicles, which indicates an increase in autophagic flux. In addition, cannabidiol-treated cells showed a reduction in cytosolic α-synuclein levels. These effects were inhibited when the cells were treated with a CB1 receptor-selective antagonist, which indicates that the biological effects of cannabidiol are mediated via its interaction with CB1 receptor. Additionally, we also observed that cannabinoid compounds induce autophagy and α-synuclein degradation after they interact with the CB1 receptor.

In summary, our data suggest that cannabidiol induces autophagy and reduces cytosolic α-synuclein levels. These biological effects are mediated preferentially through the interaction of cannabidiol with CB1 receptors, and therefore, cannabinoid compounds that act selectively on this receptor could represent a new approach for autophagy modulation and degradation of protein aggregates.”

https://pubmed.ncbi.nlm.nih.gov/39710053/

https://www.sciencedirect.com/science/article/pii/S0006899324006693?via%3Dihub

Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy

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“Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson’s disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis.

Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc.

Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling.

Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.”

https://pubmed.ncbi.nlm.nih.gov/39487447/

“Cannabinoids have emerged as promising neuroprotective agents given their ability to work as pleiotropic compounds against the multiple events that affect neural cell homeostasis, integrity and survival in conditions of brain damage and neurodegeneration.”

https://behavioralandbrainfunctions.biomedcentral.com/articles/10.1186/s12993-024-00256-9

Therapeutic potentials of cannabidiol: Focus on the Nrf2 signaling pathway

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“Cannabidiol (CBD), a cannabinoid that does not create psychoactive activities, has been identified as having a multitude of therapeutic benefits.

This study delves into the chemical properties, pharmacokinetics, safety and toxicity, pharmacological effects, and most importantly, the association between the therapeutic potential of CBD and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.

The relationship between Nrf2 and CBD is closely linked to certain proteins that are associated with cardiovascular dysfunctions, cancers, and neurodegenerative conditions. Specifically, Nrf2 is connected to the initiation and progression of diverse health issues, including nephrotoxicity, bladder-related diseases, oral mucositis, cancers, obesity, myocardial injury and angiogenesis, skin-related inflammations, psychotic disorders, neuropathic pain, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, neuroinflammation, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.

The association between CBD and Nrf2 is a zone of great interest in the medical field, as it has the potential to significantly impact the treatment and prevention of wide-ranging health conditions. Additional investigation is necessary to entirely apprehend the mechanisms underlying this crucial interplay and to develop effective therapeutic interventions.”

https://pubmed.ncbi.nlm.nih.gov/39491419/

“CBD plays a protective role in cardiovascular dysfunctions, cancers, and neurodegenerative conditions by targeting the Nrf2 signaling pathway.”

https://www.sciencedirect.com/science/article/pii/S0753332223016037?via%3Dihub

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders

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“For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times.

The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson’s disease, epilepsy, Alzheimer’s disease, and other Neurological disorders.

Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2.

While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively.

As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.”

https://pubmed.ncbi.nlm.nih.gov/39410886/

https://www.eurekaselect.com/article/143747

Use of phytocanabinoids in animal models of parkinson’s disease: systematic review

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“This systematic review was carried out with the aim of evaluating the use of medicinal Cannabis for the treatment of Parkinson’s disease in experimental models. Furthermore, we sought to understand the main intracellular mechanisms capable of promoting the effects of phytocannabinoids on motor disorders, neurodegeneration, neuroinflammation and oxidative stress.

The experimental models were developed in mice, rats and marmosets. There was a predominance of using only males in relation to females; in three studies, the authors evaluated treatments in males and females. Drugs were used as inducers of Parkinson’s disease: 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), lipopolysaccharide (LPS), and rotenone. Substances capable of promoting catalepsy in animals were also used: haloperidol, L-nitro-N-arginine (L-NOARG), WIN55,212-2, and reserpine. The inducing agent was injected stereotaxically or intraperitoneally. The most commonly used treatments were cannabidiol (CBD), Delta-9-tetrahydrocannabinol (Δ-9 THC) and Delta-9-tetrahydrocannabivarin (Δ-9 THCV), administered intraperitoneally, orally, subcutaneously and intramuscularly.

The use of phytocannabinoids improved locomotor activity and involuntary movement and reduced catalepsy. There was an improvement in the evaluation of dopaminergic neurons, while in relation to dopamine content, the treatment had no effect. Inflammation, microglial/astrocyte activation and oxidative stress were reduced after treatment with phytocannabinoids, the same was observed in the results of tests for allodynia and hyperalgesia.”

https://pubmed.ncbi.nlm.nih.gov/39182852/

https://www.sciencedirect.com/science/article/abs/pii/S0161813X24000986?via%3Dihub

Potential Neuroprotective Effect of the Endocannabinoid System on Parkinson’s Disease

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“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated.

The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment.

This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons.”

https://pubmed.ncbi.nlm.nih.gov/39104613/

“Considering current evidence, the ECS emerges as a promising therapeutic target for managing PD, primarily owing to its neuroprotective effects, prominently mediated through anti-inflammatory mechanisms. This is particularly significant since neuroinflammation stands out as a hallmark of PD, and extensive preclinical studies have consistently demonstrated that modulating this inflammatory process mitigates the progression of dopaminergic neuronal death.”

https://onlinelibrary.wiley.com/doi/10.1155/2024/5519396

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson’s Disease

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“The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson’s disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.”

https://pubmed.ncbi.nlm.nih.gov/39126088/

“The above indicates the undoubted therapeutic potential of the modulation of the ECS in PD . In recent decades, the ECS has attracted considerable interest as a potential therapeutic target for numerous disorders of the nervous system. Since PD is, clinically, a very polymorphic condition with a variety of motor and non-motor manifestations, it is a useful kind of “model” for assessing the multidimensional action of ECS modulators and is an adequate object for studying the cellular and molecular mechanisms of their action.

Cannabinoids and endocannabinoids hold promise as disease modifiers for the prevention or treatment of neurodegenerative diseases. Experimental and clinical experiences of using ECS modulators in PD and other neurodegenerative diseases create a basis for further intensive therapeutic studies of cannabis and its derivatives in chronic neurodegeneration.”

https://www.mdpi.com/1422-0067/25/15/8520

In the weeds: A comprehensive review of cannabis; its chemical complexity, biosynthesis, and healing abilities

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“For millennia, various cultures have utilized cannabis for food, textile fiber, ethno-medicines, and pharmacotherapy, owing to its medicinal potential and psychotropic effects. An in-depth exploration of its historical, chemical, and therapeutic dimensions provides context for its contemporary understanding. The criminalization of cannabis in many countries was influenced by the presence of psychoactive cannabinoids; however, scientific advances and growing public awareness have renewed interest in cannabis-related products, especially for medical use.

Described as a ‘treasure trove,’ cannabis produces a diverse array of cannabinoids and non-cannabinoid compounds. Recent research focuses on cannabinoids for treating conditions such as anxiety, depression, chronic pain, Alzheimer’s, Parkinson’s, and epilepsy. Additionally, secondary metabolites like phenolic compounds, terpenes, and terpenoids are increasingly recognized for their therapeutic effects and their synergistic role with cannabinoids. These compounds show potential in treating neuro and non-neuro disorders, and studies suggest their promise as antitumoral agents. This comprehensive review integrates historical, chemical, and therapeutic perspectives on cannabis, highlighting contemporary research and its vast potential in medicine.”

https://pubmed.ncbi.nlm.nih.gov/39056093/

https://www.sciencedirect.com/science/article/pii/S2214750024000684?via%3Dihub

A journey through cannabidiol in Parkinson’s disease

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“Parkinson’s disease is a chronic neurodegenerative disorder with no known cure characterized by motor symptoms such as tremors, rigidity, bradykinesia (slowness of movement), and postural instability. Non-motor symptoms like cognitive impairment, mood disturbances, and sleep disorders often accompany the disease. Pharmacological treatments for these symptoms are limited and frequently induce significant adverse reactions, underscoring the necessity for appropriate treatment options.

Cannabidiol is a phytocannabinoid devoid of the euphoric and cognitive effects of tetrahydrocannabinol. The study of cannabidiol’s pharmacological effects has increased exponentially in recent years.

Preclinical and preliminary clinical studies suggest that cannabidiol holds therapeutic potential for alleviating symptoms of Parkinson’s disease, offering neuroprotective, anti-inflammatory, and antioxidant properties. However, knowledge of cannabidiol neuromolecular mechanisms is limited, and its pharmacology, which appears complex, has not yet been fully elucidated.

By examining the evidence, this review aims to provide and synthesize scientifically proven evidence for the potential use of cannabidiol as a novel treatment option for Parkinson’s disease. We focus on studies that administrated cannabidiol alone.

The results of preclinical trials using cannabidiol in models of Parkinson’s disease are encouraging. Nevertheless, drawing firm conclusions on the therapeutic efficacy of cannabidiol for patients is challenging.

Cannabidiol doses, formulations, outcome measures, and methodologies vary considerably across studies. Though, cannabidiol holds promise as a novel therapeutic option for managing both motor and non-motor symptoms of Parkinson’s disease, offering hope for improved quality of life for affected individuals.”

https://pubmed.ncbi.nlm.nih.gov/39029991/

“Understanding the therapeutic potential of CBD in neurological disorders is of paramount importance, as it has the potential to provide patients with effective and well-tolerated treatment options. With significant research, CBD has the potential to meet the healthcare needs of different groups of neurological and psychiatric patients.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224000679?via%3Dihub

Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits

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“Neurodegenerative disorders (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation.

Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo.

Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.”

https://pubmed.ncbi.nlm.nih.gov/38969143/

https://www.sciencedirect.com/science/article/abs/pii/S1568163724002046?via%3Dihub