Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease.

 Image result for molecules journal“Parkinson’s disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration.

Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death.

Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system-particularly an upregulation in the immunomodulatory CB2 receptor-have been demonstrated to be related to the microglial activation state and hence the microglial phenotype.

This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31973235

“Microglia activation states and cannabinoid system: Therapeutic implications.  There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/27373505

“These findings imply that a hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of these diseases. Scientific evidence shows that cannabis can provide symptomatic relief in several neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070159/

“Cannabinoids can have neuroprotective effects, and this can be exploited for therapeutic strategies against neurodegenerative diseases”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243800/

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Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus.

antioxidants-logo “Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed.

RESULTS:

Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis.

CONCLUSION:

The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31941059

https://www.mdpi.com/2076-3921/9/1/71

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Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.

“Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine.

This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations.

Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects.

OBJECTIVE:

Herein, brain-targeting strategies for the nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties.

CONCLUSION:

Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.”

https://www.ncbi.nlm.nih.gov/pubmed/31939728

http://www.eurekaselect.com/178321/article

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Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer’s Disease Lymphoblast Alterations.

“Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including senile plaques, neurofibrillary tangles, and neuronal loss.

There are no disease-modifying drugs currently available. With the number of affected individuals increasing dramatically throughout the world, there is obvious urgent need for effective treatment strategy for AD.

The multifactorial nature of AD encouraged the development of multifunctional compounds, able to interact with several putative targets. Here, we have evaluated the effects of two in-house designed cannabinoid receptors (CB) agonists showing inhibitory actions on β-secretase-1 (BACE-1) (NP137) and BACE-1/butyrylcholinesterase (BuChE) (NP148), on cellular models of AD, including immortalized lymphocytes from late-onset AD patients.

We report here that NP137 and NP148 showed neuroprotective effects in amyloid-β-treated primary cortical neurons, and NP137 in particular rescued the cognitive deficit of TgAPP mice. The latter compound was able to blunt the abnormal cell response to serum addition or withdrawal of lymphoblasts derived from AD patients.

It is suggested that NP137 could be a good drug candidate for future treatment of AD.”

https://www.ncbi.nlm.nih.gov/pubmed/31898159

https://link.springer.com/article/10.1007%2Fs12035-019-01813-4

“The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway.” http://www.ncbi.nlm.nih.gov/pubmed/25147120

“These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.” http://www.ncbi.nlm.nih.gov/pubmed/25024327

“In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD” http://www.ncbi.nlm.nih.gov/pubmed/25147120

“Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.” http://www.ncbi.nlm.nih.gov/pubmed/15728830

“Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects.” http://www.ncbi.nlm.nih.gov/pubmed/22448595

“CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy.” http://www.ncbi.nlm.nih.gov/pubmed/27471947

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Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.

 SAGE Journals“Pantothenate kinase-associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase-associated neurodegeneration.

METHODS:

A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase-associated neurodegeneration.

RESULTS:

We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1).

CONCLUSION:

Cannabis use was commonly reported among children with pantothenate kinase-associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31823681

https://journals.sagepub.com/doi/abs/10.1177/0883073819890516?journalCode=jcna

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The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling.

 “Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer’s disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear.

WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion.

These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31808139

https://link.springer.com/article/10.1007%2Fs12640-019-00141-8

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The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling.

 “Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation.

WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders.

The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization.

The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning.

This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats.

Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630.

Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31732924

https://link.springer.com/article/10.1007%2Fs12031-019-01429-2

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Cannabidiol Protects Dopaminergic Neuronal Cells from Cadmium.

ijerph-logo“The protective effect of cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, against neuronal toxicity induced by cadmium chloride (CdCl2 10 μM) was investigated in a retinoic acid (RA)-differentiated SH-SY5Y neuroblastoma cell line.

CBD (1 μM) was applied 24 h before and removed during cadmium (Cd) treatment. In differentiated neuronal cells, CBD significantly reduced the Cd-dependent decrease of cell viability, and the rapid reactive oxygen species (ROS) increase.

CBD significantly prevented the endoplasmic reticulum (ER) stress (GRP78 increase) and the subcellular distribution of the cytochrome C, as well as the overexpression of the pro-apoptotic protein BAX. Immunocytochemical analysis as well as quantitative protein evaluation by western blotting revealed that CBD partially counteracted the depletion of the growth associated protein 43 (GAP43) and of the neuronal specific class III β-tubulin (β3 tubulin) induced by Cd treatment.

These data showed that Cd-induced neuronal injury was ameliorated by CBD treatment and it was concluded that CBD may represent a potential option to protect neuronal cells from the detrimental effects of Cd toxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/31718076

https://www.mdpi.com/1660-4601/16/22/4420

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Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.

Image result for bmj open“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis.

The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS.

Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS.

There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31719072

https://bmjopen.bmj.com/content/9/11/e029449

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Effects of Cannabis and Its Components on the Retina: A Systematic Review.

 Publication Cover“Cannabis is the most prevalent drug in the world and its consumption is growing. Cannabinoid receptors are present in the human central nervous system. Recent studies show evidence of the effects of cannabinoids on the retina, and synthesizing the results of these studies may be relevant for ophthalmologists. Thus, this review adopts standardized, systematic review methodology to investigate the effects of exposure to cannabis and components on the retina.

RESULTS:

We retrieved 495 studies, screened 229 studies, assessed 52 studies for eligibility, and included 16 studies for qualitative analysis. The cannabinoids most frequently investigated were delta-9-tetrahydrocannabinol (THC), abnormal cannabidiol, synthetic cannabinoid, and cannabidiol (CDB). The outcomes most studied were neuroretinal dysfunction, followed by vascular effects. The studies also included investigation of neuroprotective and anti-inflammatory effects and teratogenic effects.

CONCLUSIONS:

This review suggests that cannabinoids may have an important role in retinal processing and function.”

https://www.ncbi.nlm.nih.gov/pubmed/31648567

https://www.tandfonline.com/doi/abs/10.1080/15569527.2019.1685534?journalCode=icot20

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