Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

“Cannabinoids protect neurons from excitotoxic injury…

Endogenous or exogenous cannabinoids have shown neuroprotective effects…

The main finding reported here is that cannabinoids protect neurons from excitotoxic injury by a mechanism that involves the activation of CB1R and inhibition of NOS and PKA….

Cannabinoid receptor agonist drugs protect neurons…

By identifying the signaling pathways responsible for cannabinoid effects in animal models of disease and their human counterparts, it may be possible to design more specific and therefore more efficacious cannabinoid-based therapies.”

http://molpharm.aspetjournals.org/content/69/3/691.long

Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/17140550

Effect of Marijuana Use on Outcomes in Traumatic Brain Injury.

“Traumatic brain injury (TBI) is associated with significant morbidity (sickness) and mortality (death).

Several studies have demonstrated neuroprotective effects of cannabinoids.

The objective of this study was to establish a relationship between the presence of a positive toxicology screen for tetrahydrocannabinol (THC) and mortality after TBI…

After adjusting for differences between the study cohorts on logistic regression, a THC(+) screen was independently associated with survival after TBI.

A positive THC screen is associated with decreased mortality in adult patients sustaining TBI.”

http://www.ncbi.nlm.nih.gov/pubmed/25264643

http://www.thctotalhealthcare.com/category/brain-trauma/

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury.

“One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death.

Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes.

Among them, the endocannabinoid system emerges as a natural system of neuroprotection.

The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant.

The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.”

http://www.ncbi.nlm.nih.gov/pubmed/25206720

Mechanisms of control of neuron survival by the endocannabinoid system.

“Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB(1) cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival.

Thus, CB(1) 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.

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 CB(2) cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation.

Altogether, these findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.”

http://www.ncbi.nlm.nih.gov/pubmed/18781978

Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice

  Fig. 1.

“…endogenous cannabinoid signaling mechanisms may represent a key component of cell-survival programs mobilized in the injured brain.

In addition to their neuroprotective effects, cannabinergic systems may also have an important role in brain development…

…expression of endocannabinoids and cannabinoid receptors in brain…

Neurogenesis, or the birth of new neurons, continues to occur beyond development and into adulthood, and several lines of evidence suggest that cannabinoid signaling may be involved in this process as well…

In addition to the well known effects of growth factors, a variety of drugs has been shown to influence adult neurogenesis. These include excitatory amino acid receptor antagonists, antidepressants, lithium, nitric oxide donors, phosphodiesterase inhibitors, and statins.

Together with the finding that neurogenesis can be regulated by cannabinoids, these observations imply that a broad range of pharmacological approaches may exist through which to modify neurogenesis for therapeutic purposes.”

http://molpharm.aspetjournals.org/content/66/2/204.full

Marijuana May Grow Neurons in the Brain

Medpage Today

“Advocates for medical marijuana can take heart over the findings of two Canadian research teams.

A synthetic cannabinoid — similar to the compounds found in marijuana, but substantially stronger — causes the growth of new neurons and reduces anxiety and depression, investigators at the University of Saskatchewan here reported.

And researchers at the University of Calgary said they’ve found evidence that the brain contains so-called CB2 cannabinoid receptors, previously seen in immune tissue but thought not to exist in brain tissue. The discovery, they added, could lead to new drugs to treat nausea associated with cancer or AIDS.

Most so-called drugs of abuse — such as alcohol or cocaine — inhibit the growth of new neurons, according to Xia Zhang, M.D., Ph.D., of the University of Saskatchewan.

“Only marijuana promotes neurogenesis,” Dr. Zhang said.”

http://www.medpagetoday.com/Psychiatry/AnxietyStress/1934

“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects… In summary, since adult hippocampal neurogenesis is suppressed following chronic administration of opiates, alcohol, nicotine, and cocaine, the present study suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic administration.”  http://www.jci.org/articles/view/25509

University Of Saskatchewan Research Suggests Marijuana Analogue Stimulates Brain Cell Growth

ScienceDaily: Your source for the latest research news

“A synthetic substance similar to ones found in marijuana stimulates cell growth in regions of the brain associated with anxiety and depression, pointing the way for new treatments for these diseases, according to University of Saskatchewan medical research published today in The Journal of Clinical Investigation.

Xia Zhang, an associate professor in the U of S neuropsychiatry research unit, led the team that tested the effects of HU-210, a potent synthetic cannabinoid similar to a group of compounds found in marijuana. The synthetic version is about 100 times as powerful as THC, the compound responsible for the high experienced by recreational users.

The team found that rats treated with HU-210 on a regular basis showed neurogenesis – the growth of new brain cells in the hippocampus. This region of the brain is associated with learning and memory, as well as anxiety and depression.

The effect is the opposite of most legal and illicit drugs such as alcohol, nicotine, heroin, and cocaine.

“Most ‘drugs of abuse’ suppress neurogenesis,” Zhang says. “Only marijuana promotes neurogenesis.””

http://www.sciencedaily.com/releases/2005/10/051016083817.htm

“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects… In summary, since adult hippocampal neurogenesis is suppressed following chronic administration of opiates, alcohol, nicotine, and cocaine, the present study suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic administration.”  http://www.jci.org/articles/view/25509

Researchers study neuroprotective properties in cannabis

“With more states opting to legalize the sale of medical marijuana, researchers are taking a closer look at the use of cannabis to treat chronic illnesses.

Dr. Manny Alvarez, senior managing health editor of FoxNews.com, recently sat down with the Medicine Hunter, Chris Kilham, to find out how it’s being studied.

Dr. Manny: Now from the medical marijuana perspective, as far as the treatment of chronic illnesses, what is it about cannabis that makes it that special?

Medicine Hunter: Well, it seems that there are primarily two things – there’s the THC, that’s what people associated with getting high. And that appears to have a saliatory effect on the eyes in case of glaucoma. For people who are suffering from chemotherapy and can’t eat, it helps to get their appetite back. And we also know that it is a potent pain reliever – and science on that goes back to the 1890s.

But there’s another agent in cannabis that is getting more attention now, and that is called cannabidiol. And this is something that you can swallow by the bucket-full, and it won’t get you high at all. But it appears to have profound nerve-protective and brain-enhancing properties. And interestingly enough, it also induces an anti-anxiety effect.

So this appears to be a very important agent, perhaps useful in the treatment of neurodegenerative disorders.

DM: Are they extracting that particular chemical off the marijuana?

MH: There seem to be two pathways that people are taking.  You’ve got G.W. pharmaceuticals in Britain that has come out with a whole cannabis fluid spray. You’ve got people also isolating cannabidiol and playing with that in the lab.

I don’t know how this is all going to settle out – I mean, as a whole-plant person, I’m inclined toward the whole extract. But it does appear that this may also have anti-cancer properties, and that’s very intriguing.

DM: Is marijuana addictive?

MH: I would say that people can absolutely become dependent upon it.  But not physiologically addictive.  And, as you know, that’s not just parsing terms – I mean physiological addiction, you go through very grave withdrawal.

But people can become dependent on it just as they can on any substance.

DM: Tell me about this study in the American Journal of Pediatrics talking about pregnant Jamaican women and the use of pot.

MH: Melanie Dreher, who is the dean of nursing at Rush Medical Center inChicago, did a study in Jamaica. It was actually published in the American Journal of Pediatrics in 1994, but now it’s re-circulating because of all the interest in the neuroprotective properties.

Basically, she studied women during their entire pregnancy, and then studied the babies about a year after birth. And what she studied was a group of women who did smoke cannabis during pregnancy and those who didn’t. She expected to see a difference in the babies as far as birth weight and neuro tests, but there was no difference whatsoever. The differences that the researchers did notice, that are unexplained and kind of curious are that the babies of the women who had smoked cannabis — and we’re talking about daily use during their pregnancy — socialized more quickly, made eye contact more quickly and were easier to engage.

We don’t know why this is so, but all the old saws of smoking during pregnancy will result in low birth weight did not show up — at least in the Jamaican study. In U.S. studies where we’ve seen a similar investigation, women have concurrently been abusing alcohol and other drugs as well.

Alvarez said it’s interesting to note that there may be neuroprotective properties present in cannabis and the cannibidiol extract, but that smoking of any kind in pregnant women is discouraged.”

More research is needed when it comes to medical marijuana, he added.”

http://www.foxnews.com/health/2012/03/20/researchers-study-neuroprotective-properties-in-cannabis/

“Study: Cannabis may prevent brain damage” http://www.foxnews.com/health/2013/06/06/study-cannabis-may-prevent-brain-damage/

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury.

“Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae.

Because of the fact that there is still no specific treatment for perinatal brain lesions due to the complexity of neonatal hypoxic-ischemic pathophysiology, the search of new neuroprotective therapies is of great interest.

In this regard, therapeutic possibilities of the endocannabinoid system have grown lately.

The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant.

Concerning perinatal asphyxia, the neuroprotective role of this endogenous system is emerging these years.

The present review mainly focused on the current knowledge of the cannabinoids as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.

http://www.ncbi.nlm.nih.gov/pubmed/21788999

[The cannabinoid system and its importance in the perinatal period].

“The cannabinoid system has been recently described, including the endogenous ligands, mainly arachidonic acid derivatives, and their specific receptors. Endocannabinoids are involved in the modulation of synaptic transmission, through which they exert their psychoactive, motor and antinociceptive effects, among others; they also exert extraneural effects, mainly immunomodulation and vasodilation.

Recent data suggest that the cannabinoid system might play an important role in human ontogeny and could participate in the implantation and early development of the embryo, in fetal brain development, and in the beginning of breast feeding after birth.

In addition, the vasodilatory effect of cannabinoids, together with inhibition of the release of excitotoxic amino acids and cytokines, as well as modulation of oxidative stress and the toxic production of nitric oxide, justify the growing evidence pointing to a possible neuroprotective effect of cannabinoids in perinatal asphyxia.”

http://www.ncbi.nlm.nih.gov/pubmed/16266619