Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease.

“The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent.

The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition.

It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in microglia and in immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated migroglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD.

The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.”

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An overview of the cannabinoid type 2 receptor system and its therapeutic potential.

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“This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions.

RECENT FINDINGS:

The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease.

SUMMARY:

The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/29794855

https://insights.ovid.com/crossref?an=00001503-900000000-98981

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Cannabinoid-induced increase of quantal size and enhanced neuromuscular transmission.

Scientific Reports

“Cannabinoids exert dynamic control over many physiological processes including memory formation, cognition and pain perception. In the central nervous system endocannabinoids mediate negative feedback of quantal transmitter release following postsynaptic depolarization. The influence of cannabinoids in the peripheral nervous system is less clear and might have broad implications for the therapeutic application of cannabinoids. We report a novel cannabinoid effect upon the mouse neuromuscular synapse: acutely increasing synaptic vesicle volume and raising the quantal amplitudes. In a mouse model of myasthenia gravis the cannabinoid receptor agonist WIN 55,212 reversed fatiguing failure of neuromuscular transmission, suggesting future therapeutic potential. Our data suggest an endogenous pathway by which cannabinoids might help to regulate transmitter release at the neuromuscular junction.”

https://www.ncbi.nlm.nih.gov/pubmed/29549349

“Here we reveal evidence of their involvement in regulating neuromuscular transmission, and a possible therapeutic potential for cannabinoid signaling in myasthenia gravis. Our results suggest that cannabinoids might play a role in sustaining neuromuscular transmission.”

https://www.nature.com/articles/s41598-018-22888-4

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Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects.

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“The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/29169951

http://www.sciencedirect.com/science/article/pii/S0024320517306069

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Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors.

Elsevier

“Of the druggable group of G protein-coupled receptors in the human genome, a number remain which have yet to be paired with an endogenous ligand-orphan GPCRs. Among these 100 or so entities, 3 have been linked to the cannabinoid system. GPR18, GPR55, and GPR119 exhibit limited sequence homology with the established CB1 and CB2 cannabinoid receptors. However, the pharmacology of these orphan receptors displays overlap with CB1 and CB2 receptors, particularly for GPR18 and GPR55. The linking of GPR119 to the cannabinoid receptors is less convincing and emanates from structural similarities of endogenous ligands active at these GPCRs, but which do not cross-react. This review describes the evidence for describing these orphan GPCRs as cannabinoid receptor-like receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28826536

http://www.sciencedirect.com/science/article/pii/S1054358917300418?via%3Dihub

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Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

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“The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection.

The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies.

The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28788104

http://www.mdpi.com/1422-0067/18/8/1669

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Cannabinoid system of dorsomedial telencephalon modulates behavioral responses to noxious stimulation in the fish Leporinus macrocephalus.

Physiology & Behavior

“Fish dorsomedial telencephalon has been considered a pallial region homologous to mammals amygdala, being considered a possible substrate for nociception modulation in this animal group. The present study aimed to evaluate the participation of the cannabinoid system of Dm telencephalon on nociception modulation in the fish Leporinus macrocephalus. We demonstrated that cannabidiol microinjection in Dm telecephalon inhibits the behavioral nociceptive response to the subcutaneous injection of 3% formaldehyde, and this antinociception is blocked by previous treatment with AM251 microinjection. Furthermore, AM251 microinjection in Dm prior to restraint stress also blockades the stress-induced antinociception. These results reinforce the hypothesis that this pallial telencephalic structure has a pivotal role in nociception modulation in fish.”

https://www.ncbi.nlm.nih.gov/pubmed/28754268

http://www.sciencedirect.com/science/article/pii/S0031938417302299?via%3Dihub

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Delta-9-tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation.

European Journal of Pain

“This study investigated whether intramuscular injection of delta-9-tetrahydrocannabinol (THC), by acting on peripheral cannabinoid (CB) receptors, could decrease nerve growth factor (NGF)-induced sensitization in female rat masseter muscle; a model which mimics the symptoms of myofascial temporomandibular disorders.

It was found that CB1 and CB2 receptors are expressed by trigeminal ganglion neurons that innervate the masseter muscle and also on their peripheral endings.

These results suggest that reduced inhibitory input from the peripheral cannabinoid system may contribute to NGF-induced local myofascial sensitization of mechanoreceptors. Peripheral application of THC may counter this effect by activating the CB1 receptors on masseter muscle mechanoreceptors to provide analgesic relief without central side effects.

SIGNIFICANCE:

Our results suggest THC could reduce masticatory muscle pain through activating peripheral CB1 receptors. Peripheral application of cannabinoids could be a novel approach to provide analgesic relief without central side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28722246

http://onlinelibrary.wiley.com/doi/10.1002/ejp.1085/abstract

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Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.

Epilepsia

“Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates.

We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats.

The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ.

Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority.

These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.” https://www.ncbi.nlm.nih.gov/pubmed/28691158

http://onlinelibrary.wiley.com/doi/10.1111/epi.13842/abstract

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Brain cannabinoid systems as targets for the therapy of neurological disorders.

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“Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.” https://www.ncbi.nlm.nih.gov/pubmed/9974182 

“Endocannabinoid System in Neurological Disorders.” https://www.ncbi.nlm.nih.gov/pubmed/27364363
“Cannabinoids in the Treatment of Neurological Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604187/
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