Tag Archives: neuroprotective

Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome.

Posted on by
Reply

Image result for Pediatr Neurol

“Sturge-Weber syndrome results in leptomeningeal vascular malformations, medically refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol, a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, antioxidant, and neuroprotective actions.

CONCLUSION:

This study suggests that cannabidiol may be well tolerated as adjunctive medication for seizure management and provides initial data supporting further study of cannabidiol in individuals with Sturge-Weber syndrome.”

https://www.ncbi.nlm.nih.gov/pubmed/28454984

Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol – studies in BV-2 microglia and encephalitogenic T cells

Posted on by
Reply

“Preparations derived from Cannabis sativa (marijuana and hashish) have become widespread since ancient times, both as therapeutic agents and in recreational smoking.

Among the more than 60 phytocannabinoids identified in Cannabis extracts, the two most abundant are Δ9-tetrahydrocannabinol (THC), the major psychotropic constituent, and cannabidiol (CBD), the major non-psychoactive component.

Cannabinoids were shown to exert a wide range of therapeutic effects, and many of the cannabinoids, especially CBD, were shown to possess potent anti-inflammatory and immunomodulatory activities. In addition, it was shown that several cannabinoids have pro-apoptotic, neuroprotective, and antitumor properties

Dimethylheptyl-cannabidiol (DMH-CBD), a non-psychoactive, synthetic derivative of the phytocannabinoid cannabidiol (CBD), has been reported to be anti-inflammatory in RAW macrophages. Here, we evaluated the effects of DMH-CBD at the transcriptional level in BV-2 microglial cells as well as on the proliferation of encephalitogenic T cells.

The results show that DMH-CBD has similar anti-inflammatory properties to those of CBD. DMH-CBD downregulates the expression of inflammatory cytokines and protects the microglial cells by inducing an adaptive cellular response against inflammatory stimuli and oxidative injury. In addition, DMH-CBD decreases the proliferation of pathogenic activated TMOG cells.

Several CBD derivatives were also shown to have anti-inflammatory and anti-proliferative properties.

The results show that DMH-CBD induces similar anti-inflammatory, anti-proliferative, and stress response effects to those previously observed for CBD.”

https://www.degruyter.com/view/j/jbcpp.2016.27.issue-3/jbcpp-2015-0071/jbcpp-2015-0071.xml

Editorial: The CB2 Cannabinoid System: A New Strategy in Neurodegenerative Disorder and Neuroinflammation

Posted on by
Reply

Image result for frontiers in neuroscience

“The cannabinoid receptors subtype 2 (CB2R) are emerging as novel targets for the development of new therapeutic approaches and PET probes useful to early diagnose neuroinflammation as first step in several neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson disease (PD).

This Research Topic is mainly focused on the involvment of CB2R in neurodegenerative disorders and on the usefulness of CB2R ligands in the therapy and early diagnosis of neuroinflammation as onset of neurodegeneration.

In the reviews of Aso and Ferrer and Cassano et al. an interesting and exaustive overview of the endogenous cannabinoid signaling and its role in neuroinflammation and neurogenesis is reported. The potential of CB2R as therapeutic target in AD is argued by several evidences derived by robust experimental models and the effects modulated by CB2R agonists on different pathways involved in the pathogenesis of AD are discussed; indeed, these ligands are able to reduce inflammation, Aβ production and deposition, tau protein hyper-phosphorylation and oxidative stress damage caused by Aβ peptides. CB2R agonists are also able to induce Aβ clearance leading to cognitive improvement in AD models.

In conclusion, considering that neuroinflammation has been widely reported as indicator and modulator of neurodegeneration, the reduction of the neuroinflammatory responses could be considered as a new therapeutic strategy in these diseases. Moreover, the selective CB2R overexpression on the activated-microglial cells provides also a highly specialized target useful to an early diagnosis of the neurodegenerative diseases.”

http://journal.frontiersin.org/article/10.3389/fnins.2017.00196/full

Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions.

Posted on by
Reply

 Image result for Rev Physiol Biochem Pharmacol.

“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids.

In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment.

For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system.

Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment.

This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/28425013

Neurological aspects of medical use of cannabidiol.

Posted on by
Reply

Image result for CNS Neurol Disord Drug Targets.

“Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activi-ties and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.

OBJECTIVE:

Aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.

RESULTS:

Laboratory and clinical studies on the potential role of CBD in Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.

CONCLUSIONS:

Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.”

https://www.ncbi.nlm.nih.gov/pubmed/28412918

Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.

Posted on by
Reply

Image result for neuropharmacology journal

“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points.

The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined.

The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1G93A mouse model of ALS.

We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro.

In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28373073

Protective Effects of Cannabidiol against Seizures and Neuronal Death in a Rat Model of Mesial Temporal Lobe Epilepsy.

Posted on by
Reply

Image result for Front Pharmacol

“The present study reports the behavioral, electrophysiological, and neuropathological effects of cannabidiol (CBD), a major non-psychotropic constituent of Cannabis sativa, in the intrahippocampal pilocarpine-induced status epilepticus (SE) rat model. Our findings demonstrate anticonvulsant and neuroprotective effects of CBD preventive treatment in the intrahippocampal pilocarpine epilepsy model, either as single or multiple administrations, reinforcing the potential role of CBD in the treatment of epileptic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28367124

“This study showed that CBD treatment reduces the behavioral severity and oscillatory electrographic changes of SE, the post-ictal lethargy, and the neuronal loss associated with the pilocarpine-induced SE rat model. More studies are needed to understand the specific mechanisms of action related to the neuroprotective and anticonvulsant effects of CBD in epilepsy.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355474/

In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study.

Posted on by
Reply

Image result for journal of neuroinflammation

“Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET).

CONCLUSIONS:

The present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes.” https://www.ncbi.nlm.nih.gov/pubmed/28356120

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0851-4

Loss of Cannabinoid CB 1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility.

Posted on by
Reply

Image result for cerebral cortex journal

“Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB 1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB 1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB 1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB 1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.”

https://www.ncbi.nlm.nih.gov/pubmed/28334226

Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors.

Posted on by
Reply

 Image result for Am J Transl Res

“The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity.

Actually, CBr agonists can be neuroprotective.

Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28337258