Posts tagged cannabinoids
Blocking brain’s ‘internal marijuana’ may trigger early Alzheimer’s deficits
A new study led by investigators at the Stanford University School of Medicine has implicated the blocking of endocannabinoids — signaling substances that are the brain’s internal versions of the psychoactive chemicals in marijuana and hashish — in the early pathology of Alzheimer’s disease.
A substance called A-beta — strongly suspected to play a key role in Alzheimer’s because it’s the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer’s — may, in the disease’s earliest stages, impair learning and memory by blocking the natural, beneficial action of endocannabinoids in the brain, the study demonstrates. The Stanford group is now trying to figure out the molecular details of how and where this interference occurs. Pinning down those details could pave the path to new drugs to stave off the defects in learning ability and memory that characterize Alzheimer’s.
In the study, published June 18 in Neuron, researchers analyzed A-beta’s effects on a brain structure known as the hippocampus. In all mammals, this midbrain structure serves as a combination GPS system and memory-filing assistant, along with other duties.
“The hippocampus tells us where we are in space at any given time,” said Daniel Madison, PhD, associate professor of molecular and cellular physiology and the study’s senior author. “It also processes new experiences so that our memories of them can be stored in other parts of the brain. It’s the filing secretary, not the filing cabinet.”
Surprise finding
Applying electrophysiological techniques to brain slices from rats, Madison and his associates examined a key hippocampal circuit, one of whose chief elements is a class of nerve cells called pyramidal cells. They wanted to see how the circuit’s different elements reacted to small amounts of A-beta, which is produced throughout the body but whose normal physiological functions have until now been ill-defined.
A surprise finding by Madison’s group suggests that in small, physiologically normal concentrations, A-beta tamps down a signal-boosting process that under certain conditions increases the odds that pyramidal nerve cells will transmit information they’ve received to other nerve cells down the line.
When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input — such as might accompany falling into a hole, burning one’s finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell “cat” — are firmly stored in the brain’s memory vaults and more accessible to retrieval.
These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells — effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of “wet blanket” nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells’ transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance — the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.
Passing along the message
But when the news is particularly significant, pyramidal cells squirt out their own “no, this is important, you shut up!” chemical — endocannabinoids — which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.
A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.
While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.
Exactly how A-beta blocks endocannabinoids’ action is not yet known. But, Madison’s group demonstrated, A-beta doesn’t stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car’s ignition switch won’t do much good if your battery is dead.)
Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.
“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”
Besides, flooding the brain with external cannabinoids induces tolerance — it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids’ ability to do their crucial job of opening the gates of learning and memory.
Filed under endocannabinoids alzheimer's disease pyramidal cells cannabinoids interneurons neuroscience science
TAU researchers find chemicals in marijuana could help treat MS
Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical, and mental problems. No one knows why people get the disease or how to treat it.
In a new study published in the Journal of Neuroimmune Pharmacology, Drs. Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv University’s Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.
"Inflammation is part of the body’s natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.
Mind-altering findings
Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.
Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.
In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.
High hopes for humans
In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.
The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules’ ability to reach and damage the brain and spinal cord.
Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.
"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We’re just beginning to understand how it works."
(Source: aftau.org)
Filed under cannabinoids inflammation MS interleukin 17 endocannabinoids neuroscience science
Why good resolutions about taking up a physical activity can be hard to keep
The collective appraisal conducted by Inserm in 2008 highlighted the many preventive health benefits of regular physical activity. Such activity is limited, however, by our lifestyle in today’s industrial society. While varying degrees of physical inactivity may be partly explained by social causes, they are also rooted in biology.
“The inability to experience pleasure during physical activity, which is often quoted as one explanation why people partially or completely drop out of physical exercise programmes, is a clear sign that the biology of the nervous system is involved”, explains Francis Chaouloff.
But how exactly? The neurobiological mechanisms underlying physical inactivity had yet to be identified.
Francis Chaouloff (Giovanni Marsicano’s team at the NeuroCentre Magendie; Inserm joint research unit, Université Bordeaux Ségalen) and his team have now begun to decipher these mechanisms. Their work clearly identifies the endogenous cannabinoid (or endocannabinoid) system as playing a decisive role, in particular one of its brain receptors. This is by no means the first time that data has pointed to interactions between the endocannabinoid system, which is the target of delta9-tetrahydrocannabinol (the active ingredient of cannabis), and physical exercise. It was discovered ten years ago that physical exercise activated the endocannabinoid system in trained sportsmen, but its exact role remained a mystery for many years. Three years ago, the same research team in Bordeaux observed that when given the opportunity to use a running wheel, mutant mice lacking the CB1 cannabinoid receptor, which is the principal receptor of the endocannabinoid system in the brain, ran for a shorter time and over shorter distances than healthy mice. The research published in Biological Psychiatry this month seeks to understand how, where and why the lack of CB1 receptor reduces voluntary exercise performance (by 20 to 30%) in mice allowed access to a running wheel three hours per day.
The researchers used various lines of mutant mice for the CB1 receptor, together with pharmacological tools. They began by demonstrating that the CB1 receptor controlling running performance is located at the GABAergic nerve endings. They went on to show that the receptor is located in the ventral tegmental area of the brain, which is an area involved in motivational processes relating to reward, whether the reward is natural (food, sex) or associated with the consumption of psychoactive substances.
Filed under cannabinoids endocannabinoid system neurotransmitters physical activity physical exercise neuroscience science
