Attacking Ourselves

Human proteins added to vaccines

Synthetic proteins mimic the real thing

Effects of Cannabinoids on T lymphocyte Resistance to Infection

Cannabinoids to Treat Acute Respiratory Distress Syndrome

"The common feature of Acute Respiratory Distress Syndrome (ARDS) includes systemic hyperactivation of immune response leading to inflammation in the lungs followed by the development of pulmonary edema, alveolar damage, and respiratory failure.

There are over 200,000 people affected by ARDS annually in the US and three million people globally, and ARDS causes over 75,000 deaths in the US alone.

ARDS can result from a wide range of insults, and the precise nature of antigens or factors that trigger hyperactivation of the immune response, is unclear.

The most challenging question which remains unanswered is whether hyperactivation of immune response seen in patients with the severe form of COVID-19 results from hyperimmune response against the virus or against secondary infections seen in these patients or a combination of both.

It is less likely that the hyperactivation of the immune response is against the virus itself because these are the same patients who are immunocompromized that fail to exhibit an optimum response to the virus.

The prevalence of coinfection varies but it can account for up to 50% among patients who die from COVID-19 (Lai et al., 2020).

The copathogens include, Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and the like (Lai et al., 2020).

Some of these bacteria produce toxins such as Staphylococcus enterotoxin B (SEB) which can activate a large proportion of T lymphocytes, thereby causing cytokine storm, ARDS, and multiorgan failure."

Δ9-Tetrahydrocannabinol Prevents Mortality from Acute Respiratory Distress Syndrome

A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment.

Metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice.

THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets.

Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS.

Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.

Natural Immunity as the Master Conductor of Homeostasis

Cannabinoids Decrease the Th17 Inflammatory Autoimmune Phenotype

Modulation of cellular redox homeostasis by the endocannabinoid system

"If you wanted to wipe out a group of people, the best way would be to disable their immune systems, making them ready victims of illness."

JD Trout

Nagalase in Blood

Cannabinoid system immune modulation

Ensuring Uptake of Vaccines against SARS-CoV-2

Observers discover novel link between immune system, social behavior

Immune System Affects Social Behaviour and Personality

Tolerance is a fundamental property of the immune system.

Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign proteins, but not self.

Autoimmunity is invoked when tolerance to autoantigens is broken.

Immunological tolerance within an individual normally begins as a fetus.

In maternal fetal tolerance T lymphocytes express receptors for a specific antigen enters the circulation of the developing fetus via the placenta.

Fetal T lymphocytes orginate in the bone marrow where they begin growth but must travel to the thymus where maturation of T lymphocytes occurs.

Within the thymus fetal T lymphocytes encounter a variety of antigens.

T lymphocytes, now attenuated to pathogens, become pathogen hunters.

Approximately 99 percent of fetal T lymphocytes die through induction of apoptosis in the thymus attempting to convert T lymphocytes into hunters.

Gut plethora of microbes

Exercise stalls cancer growth

Fasting triggers stem cell regeneration

Modulation of Adult Hippocampal Neurogenesis:
Environmental Challenges Trigger Immune Activation

An autoimmune response can be incited through molecular mimicry.

Molecular mimicry involves the ability of similar molecular structures from dissimilar genes or proteins to mimic similar organic self structures.

Dissimilar sequence partial structures may elicite an autoimmune response.

Virulent proteins, through molecular surfaces, mimic host protein surfaces.

Through molecular mimicry a pathogen may generate natural immunity.

The pathogen may mimic the linear amino acid sequence.

It may mimic the conformational fit of the immunodominant epitope.

In the phenomenon of immunodominance immune responses are mounted against a few of the antigenic peptides presented on the globular protein.

Immunodominance epitopes exist for antibody and lymphocyte immunity.

An autoimmune response is then generated by any similar pathogen.

Pathogens alter macrophage function; act as mutagens to release cytokines.

Release of cytokines spark reformation of exosomes altering cellular DNA creating antigen release mechanisms to counteract foreign proteins.

By distorting the configuration of the native protein, the immune system attacks autoantigens, resulting in an autoimmune or allergic reaction.

Due to similar sequence homology in the immunodominant epitope between the pathogen and the host, cells and tissues of the host associated with the protein are hunted down as a result of the autoimmune response.

Findings from biological research suggest that sustained involvement in gratifying activities such as the creation of works of art or walking through Pinus sylvestris forests result in positive immune system responses.

Cannabinoids and the immune system

The effect of cannabimimetic agents on the function of immune cells such as T and β lymphocytes, large granular lymphocytes and macrophages has been extensively studied using human and animal paradigms involving whole animal models (in vivo) as well as tissue culture systems ( in vitro).

Cannabimimetic agents act as agonists at cannabinoid receptors.

Cannabimimetic agents have a complex effects on immune cell function.

Activity is mediated by cannabinoid receptors expressed on cell subtypes.

It is likely that the cannabinoid system, along with the other neuroimmune systems, has a subtle but significant role in the regulation of immunity.








Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.

Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects.

Cannabinoids as novel anti-inflammatory drugs

Conclusion: The potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T lymphocytes or other cellular immune components.

The endocannabinoid anandamide neither impairs in vitro T lymphocyte function nor induces regulatory T lymphocyte generation

Conclusion: The direct antitumor activity of AEA together with the absence of negative effects on T lymphocyte functions might provide new insights into the potential use of cannabinoid agents in cancer immunotherapy.

Inhaled medicinal cannabis and the immunocompromised patient

Conclusion: Medicinal cannabis is an invaluable adjunct therapy for pain relief, nausea, anorexia, and mood modification in cancer patients and is available as cookies or cakes, as sublingual drops, as a vaporized mist, or for smoking.

Cannabinoids and ceramide: two lipids acting hand-in-hand.

Conclusion: Sustained ceramide accumulation in tumor cells mediates cannabinoid-induced apoptosis, as evidenced by in vitro and in vivo studies.

The endocannabinoid anandamide neither impairs in vitro T lymphocyte function nor induces regulatory T lymphocyte generation.

Conclusion: Direct antitumor activity of endogenous cannabinoid anandamide together with the absence of negative effects on T lymphocyte functions.

Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids

The phytocannabinoid (-)-cannabidiol is a partial agonist, being approximately 40 fold more potent than (+)-cannabidiol; abnormal-cannabidiol is a full agonist. Furthermore, the abnormal-cannabidiol (CBD) analog trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-methyl-1,3-benzenediol (O-1602) inhibits migration, with an IC(50) value of 33 nM. This reported profile of agonist efficacy and potency parallels with the pharmacology of the novel "abnormal-cannabidiol" receptor or a related orphan G protein-coupled receptor, which are already known to modulate cell migration.

Endogenous lipids, phytocannabinoids, and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors; this target is antagonized by the endogenous compound N-arachidonoyl l-serine.


Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy

Conclusion: This small, short-term, placebo controlled trial of inhaled cannabis demonstrated a dose dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain. This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain.

Cannabis Use in Patients with Fibromyalgia

Conclusion: The use of cannabis was associated with beneficial effects on some Fibromyalgia symptoms.

Neuropathic orofacial pain: cannabinoids as a therapeutic avenue

Conclusion: Neuropathic orofacial pain (NOP) exists in several forms including pathologies such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). BMS and PIFP are classically diagnosed by excluding other facial pain syndromes. Analgesia is one the principal therapeutic targets of the cannabinoid system and many studies have demonstrated the efficacy of cannabinoid compounds in the treatment of neuropathic pain.

The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain

Conclusion: Cannabis-based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments.

Management of chronic nonmalignant neuropathic pain

Conclusion: Cannabis-based medicinal extracts used in different populations of chronic nonmalignant neuropathic pain patients may provide effective analgesia in conditions that are refractory to other treatments.


Role of interleukin-1 in general pathology

IL-1 is a master regulator of inflammation via controlling a variety of innate immune processes. Currently, human sequence algorithm technologies suggest that the IL-1 family comprises a total of 11 members with similar or distinct biological effects.

IL-1a, IL-1ß, IL-1Ra, IL-18, IL-33, IL-36a, IL-36ß, IL-36α, IL-36Ra IL-37, and IL-38 have been identified and characterized.

Among them, IL-1a, IL-1ß, IL-18, IL-33, and IL-36 are receptor-agonistic, and IL-1Ra, IL-36Ra, and IL-38 are receptor-antagonistic.

IL-37 is the only anti-inflammatory cytokine.

Although the function of each IL-1 family member is now being investigated, IL-1 is the most characterized among these members.

Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1ß (IL-1ß) signalling

Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis.

Activation of cannabinoid receptors suppresses chronic inflammatory responses through the attenuation of pro-inflammatory mediators.

The endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous system).

The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1ß (interleukin-1ß) associated signalling pathways and NSC biology, in order to develop therapeutical strategies on CNS diseases that may facilitate brain repair.

NSCs express functional CB1 and CB2 cannabinoid receptors, DAGLa (diacylglycerol lipase a) and the NSC markers SOX-2 and nestin. We have investigated the role of CB1 and CB2 cannabinoid receptors in the control of NSC proliferation and in the release of immunomodulators [IL-1ß and IL-1Ra (IL-1 receptor antagonist)] that control NSC fate decisions. Pharmacological blockade of CB1 and/or CB2 cannabinoid receptors abolish or decrease NSC proliferation, indicating a critical role for both CB1 and CB2 receptors in the proliferation of NSC via IL-1 signalling pathways. Thus the endocannabinoid system, which has neuroprotective and immunomodulatory actions mediated by IL-1 signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult NSCs, and this may be of therapeutic interest in the emerging field of brain repair.

Cannabinoid receptor CB2 is involved in tetrahydrocannabinol-induced anti-inflammation against lipopolysaccharide in MG-63 cells

Conclusion: CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.


Antibacterial cannabinoids from Cannabis sativa

Conclusion: These observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.

Cannabinoids Δ9Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-?B and Interferon-ß/STAT Proinflammatory Pathways in BV-2 Microglial Cells

Conclusion: Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases.


Involvement of the endocannabinoid system in osteoarthritis pain

Conclusion: This review summarizes the promising results that have been recently obtained in support of the therapeutic value of cannabinoids for osteoarthritis management.

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

Conclusion: Our data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.

The endocannabinoid system and its therapeutic implications in rheumatoid arthritis.

Conclusion: We discuss the possible functions of the endocannabinoid system in the modulation of RA, which may be a potential target for treatment.

Efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis

Conclusion: Significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment.

Peripheral cannabinoid receptor, CB2, regulates bone mass

Conclusion: CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries.

Osteoporosis develops when bone mineral density and bone mass decreases.

Key nutrients for bone health at all ages are calcium, protein and vitamin D.

A lack of foods that contain vital nutrients negatively affect bone density.

Rich sources of vitamin D include fatty fish, fish-liver oils and liver.

Foods fortified with vitamin D including milk, orange juice and cereals.

Drugs interfere vitamin D metabolism: steroids, dilantin and phenobarbitol.

Sodium causes an increase in renal calcium excretion.

Low potassium diets increase urinary calcium losses and high potassium diets reduce it.

Potassium is found in several vegetables, fruits, legumes and milk.

Cannabinoid WIN-55,212-2 mesylate inhibits ADAMTS-4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan-1

Accumulating evidence suggests that cannabinoids have chondroprotective effects.

Cannabinoid-based therapy as a future for joint degeneration

Apart from the above mentioned advantages of cannabinoids in chronic pain, ECS modulation itself might be a useful strategy for treating arthritis and the accompanying pain and inflammation. Although endocannabinoids are not selective for the CB2 receptor, they have been proven to diminish hyperalgesia in various arthritis animal models and prevent joint damage.

CB2 involved in anti-inflammation against lipopolysaccharide in MG-63 cells

Activation of cannabinoid receptor CB2 reduces inflammation. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS) to mimic the inflammation of OA. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factor a (TNF-a), interleukin- (IL-) 1ß, IL-6, and IL-8, decreased nuclear factor-KB (NF-KB) expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.

Cannabinoids Δ9Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-KB and Interferon-ß/STAT Proinflammatory Pathways in BV-2 Microglial Cells

The NF-KB pathway is a primary intracellular pathway controlling the transcription of many inflammatory enzymes.

We found that the two major cannabinoids present in marijuana, Δ9tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1ß, interleukin-6, and interferon (IFN)ß, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-KB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events.

Both THC and CBD decrease LPS-induced IFNß production and release. These cannabinoids exert their inhibitory activity upstream of IFNß synthesis, e.g. at the level of the MyD88-independent pathway that is leading to the activation of IRF-3. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-KB and IFNß-dependent pathways.


Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling

Conclusion: Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.

Modeling an autism risk factor in mice leads to permanent immune dysregulation.

Conclusion: These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.


The endocannabinoid system of the skin in health and disease

Conclusion: The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their guanine nucleotide-binding protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. Pathological alterations in the activity of the fine-tuned cutaneous ECS might promote or lead to the development of certain skin diseases.

Anti-inflammatory activity of topical THC

Conclusion: This has important implications for the future development of strategies to harness cannabinoids for the treatment of inflammatory skin diseases.

Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury

Skin inflammatory diseases result from complex events that include dysregulation and abnormal expression of inflammatory mediators or their receptors in skin cells. The extract inhibited the release of mediators of inflammation involved in wound healing and inflammatory processes occurring in the skin. The mode of action involved the impairment of the nuclear factor-kappa B (NF-KB) pathway since the extract counteracted the tumor necrosis factor-alpha-induced NF-KB-driven transcription in both skin cell lines. Cannabis extract and cannabidiol showed different effects on the release of interleukin-8 and vascular endothelial growth factor, which are both mediators whose genes are dependent on NF-KB. The effect of cannabidiol on the NF-KB pathway and metalloproteinase-9 (MMP-9) release paralleled the effect of the extract thus making cannabidiol the major contributor to the effect observed.

Down-regulation of enzymes involved in wound healing and skin inflammation was at least in part due to the presence of cannabidiol.

Our findings provide new insights into the potential effect of Cannabis extracts against inflammation-based skin diseases.

Differential role of cannabinoids in the pathogenesis of skin cancer

Key findings: THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment.


Δ9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesvirus in vitro

Conclusion: THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesvirus, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication.

Cannabis May Help Combat Cancer-causing Herpes virus

Conclusion: Small concentrations of THC were more potent and selective against gamma herpes virus than the commonly used antiviral drugs acyclovir, gancicyclovir and foscamet.

In WWII at least 1.5 million solders were infected,
with case fatality ranging from 0.2 -5.0%


Malaria Pathogenesis

In the mosquito-human life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 106 organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host-parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants.

Malaria Elimination

Important strides have been made within the past decade toward malaria elimination in many regions, and with this progress, the feasibility of eradication is once again under discussion. If the ambitious goal of eradication is to be achieved by 2040, all species of Plasmodium infecting humans will need to be targeted with evidence-based and concerted interventions. In this perspective, the potential barriers to achieving global malaria elimination are discussed with respect to the related diversities in host, parasite, and vector populations. We argue that control strategies need to be reorientated from a sequential attack on each species, dominated by Plasmodium falciparum to one that targets all species in parallel. A set of research themes is proposed to mitigate the potential setbacks on the pathway to a malaria-free world.

Changing epidemiology of malaria elimination

Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics.

Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.

Conclusion: Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.


Cannabis in painful HIV-associated sensory neuropathy

Conclusion: Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.

Cannabinoids inhibit migration of microglial-like cells to the HIV protein Tat

Conclusion: These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like cell migration to Tat is linked functionally to the CB2R. Furthermore, the results indicate that activation of the CB2R leads to altered expression and compartmentation of the ß-chemokine receptor CCR-3.

Cannabinoid inhibits HIV-1 Tat-stimulated adhesion of human monocyte-like cells to extracellular matrix proteins

Conclusion: The blood-brain barrier (BBB) is a complex structure that is composed of cellular elements and an extracellular matrix (ECM). HIV-1 Tat promotes transmigration of monocytes across this barrier, a process that includes interaction with ECM proteins. The results indicate that cannabinoids that activate the CB2R inhibit the ECM adhesion process. Thus, this receptor has potential to serve as a therapeutic agent for ablating neuroinflammation associated with HIV-elicited influx of monocytes across the BBB.

The multiplicity of action of cannabinoids: implications for treating neurodegeneration

The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the guanine nucleotide-binding protein coupled CB receptors, CB1 and CB2. These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands. The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis.

Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration. Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer' disease, multiple sclerosis, and cerebral ischemia.

Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

Cannabinoids protect neurons from excitotoxic injury. We investigated the mechanisms involved by studying N-methyl-d-aspartate (NMDA) toxicity in cultured murine cerebrocortical neurons in vitro and mouse cerebral cortex in vivo. Cannabinoids seem to protect neurons against NMDA toxicity at least in part by activation of CB1R and downstream inhibition of PKA signaling and NO generation.

Mechanisms of control of neuron survival by the endocannabinoid system

Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB1 cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival. Thus, CB1 receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases.

Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB1 receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB1 receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB2 cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation. These findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.

Endocannabinoids: lipid mediators involved in the regulation of neural cell development

The endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol are important retrograde messengers that inhibit neurotransmitter release via presynaptic CB1 receptors. Cannabinoids are known to modulate the cell death/survival decision of different neural cell types. Cannabinoids protect primary neurons, astrocytes and oligodendrocytes from apoptosis, whereas transformed glial cells are prone to apoptosis by cannabinoid challenge. Recent research shows that eCBs stimulate neural progenitor proliferation and inhibit hippocampal neurogenesis in normal adult brain. Cannabinoids inhibit cortical neuron differentiation and promote glial differentiation. Cannabinoids also regulate neuritogenesis, axonal growth and synaptogenesis. These new observations support that eCBs constitute a new family of lipid signaling cues responsible for the regulation of neural progenitor proliferation and differentiation, acting as instructive proliferative signals through the CB1 receptor.

Δ9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity

Cannabinoid receptor agonists act presynaptically to inhibit glutamate release. The effect of prolonged drug exposure on the neuroprotection afforded by cannabinoid receptor agonists was also studied. Desensitization of CB(1) receptors diminishes the neuroprotective effects of cannabinoids. This study demonstrates the importance of agonist efficacy and the duration of treatment on the neuroprotective effects of cannabinoids.

Neuroprotection by Δ9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity

In summary, we have shown that in an in vivo model of neurodegeneration Δ9-THC reduces neuronal damage via a CB1-receptor-mediated mechanism. This holds in both the acute and late phase after induction of excitotoxicity. Δ9-THC inhibits astrogliosis via a non-CB1-receptor-controlled mechanism. The results strengthen the concept that the endogenous cannabinoid system may serve to establish a defense system for the brain. This system may be functional in several neurodegenerative diseases in which excitotoxicity is thought to play a role, such as amyotrophic lateral sclerosis, Huntington' and Parkinson' diseases, and also in acute neuronal damage as found in stroke and traumatic brain injury. It is conceivable that the endogenous cannabinoid system can be exploited for therapeutic interventions in these types of primarily incurable diseases.

Cannabidiol Protects Dopaminergic Neuronal Cells from Cadmium

The protective effect of cannabidiol (CBD), the non-psychoactive element 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. 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.

36 natural substances help to support immune system

unique library index

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