Enhancing Activity of Marijuana-like Chemicals in Brain Helps Treat Parkinson's Symptoms in Mice
February 8, 2007
Science Daily/Stanford University Medical Center
Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson's disease. In a study to be published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.
"This study points to a potentially new kind of therapy for Parkinson's disease," said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease."
Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study's lead author, combined a drug already used to treat Parkinson's disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson's, the mice went from being frozen in place to moving around freely in 15 minutes. "They were basically normal," Kreitzer said.
But Kreitzer and Malenka cautioned that their findings don't mean smoking marijuana could be therapeutic for Parkinson's disease.
"It turns out the receptors for cannabinoids are all over the brain, but they are not always activated by the naturally occurring endocannabinoids," said Malenka. The treatment used on the mice involves enhancing the activity of the chemicals where they occur naturally in the brain. "That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."
The researchers began their study by focusing on a region of the brain known as the striatum. They were interested in that region because it has been implicated in a range of brain disorders, including Parkinson's, depression, obsessive-compulsive disorder and addiction.
The activity of neurons in the striatum relies on the chemical dopamine. A shortage of dopamine in the striatum can lead to Parkinson's disease, in which a person loses the ability to execute smooth motions, progressing to muscle rigidity, tremors and sometimes complete loss of movement. The condition affects 1.5 million Americans, according to the National Parkinson Foundation.
"It turns out that the striatum is much more complicated than imagined," said Malenka. The striatum consists of several different cell types that are virtually indistinguishable under the microscope. To uncover the individual contributions of the cell types, Malenka and Kreitzer used genetically modified mice in which the various cell types were labeled with a fluorescent protein that glows vivid green under a microscope. Having an unequivocal way to identify the cells allowed them to tease apart the functions of the different cell types.
Malenka's lab has long studied how the communication between different neurons is modified by experience and disease. In their examination of two types of mouse striatum cells, Kreitzer and Malenka found that a particular form of adaptation occurs in one cell type but not in the other.
Malenka said this discovery was exciting because no one had determined whether there were functional differences between the various cell types. Their study indicated that the two types of cells formed complementary circuits in the brain.
One of the circuits is thought to be involved in activating motion, while the other is thought to be involved in restraining unwanted movement. "These two circuits are critically involved in a push-pull to select the appropriate movement to perform and to inhibit the other," said Kreitzer.
Dopamine appears to modulate these two circuits in opposite ways. When dopamine is depleted, it is thought that the pathway responsible for inhibiting movement becomes overly activated - leading to the difficulty of initiating motion, the hallmark of Parkinson's disease.
Current treatment for Parkinson's includes drugs that stimulate or mimic dopamine. It turns out that the neurons Kreitzer identified as inhibiting motion had a type of dopamine receptor on them that the other cells didn't. The researchers tested a drug called quinpirole, which mimics dopamine, in mice with a condition similar to human Parkinson's disease, resulting in a small improvement in the mice.
"That was sort of expected," said Malenka. "The cool new finding came when we thought to use drugs that boost the activity of endocannabinoids." Based on prior knowledge of endocannabinoids and dopamine, they speculated that the two chemicals were working in concert to keep the inhibitory pathway in check.
When they added a drug that slows the enzymatic breakdown of endocannabinoids in the brain - URB597, being developed by Kadmus Pharmaceuticals in Irvine, Calif. - the results were striking.
"The dopamine drug alone did a little bit but it wasn't great, and the drug that targeted the enzyme that degrades endocannabinoids basically did nothing alone," Kreitzer said. "But when we gave the two together, the animals really improved dramatically."
This work was supported by a Ruth L. Kirchenstein Fellowship, the National Institutes of Health and the National Parkinson Foundation. Neither researcher has financial ties to Kadmus Pharmaceuticals.
https://www.sciencedaily.com/releases/2007/02/070207171915.htm
Marijuana-Like Compounds May Aid Array of Debiliatiing Conditions Ranging from Parkinson's Disease to Pain
October 27, 2004
Science Daily/Society for Neuroscience
No longer a pipe dream, new animal research now indicates that marijuana-like compounds can aid a bevy of debilitating conditions, ranging from brain disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease, to pain and obesity.
In past studies, researchers determined that the main active chemicals in the drug marijuana produce a variety of effects by connecting to specific sites on nerve cells, called cannabinoid receptors. Researchers also discovered that these receptors normally bind to natural internal chemicals, dubbed cannabinoids.
“Understanding how marijuana and the brain's own natural cannabinoid system works is helping researchers design new medicines,” says cannabinoid expert Daniele Piomelli, PhD, of the University of California in Irvine. “It's believed that the controlled therapies that come out of this research might provide select benefits to patients while avoiding some of the unwanted effects seen with the drug.”
Research from California Pacific Medical Center in San Francisco points to the promise of marijuana-like treatments for those with the fatal brain disorder ALS, also known as Lou Gehrig's disease.
“Our research indicates that select marijuana compounds, including THC, significantly slow the disease process and extend the life of mice with ALS,” says study author Mary Abood, PhD.
The study extends earlier work from Abood's group that found that THC also can alleviate some ALS symptoms, like muscle spasms, in patients.
ALS wreaks its havoc by harming nerve cells that control muscles. As a consequence of the damage, an estimated 5,000 Americans afflicted annually experience progressive muscle weakness that can hinder movement, speech, even swallowing and breathing. New treatments for ALS are desperately needed.
“The only FDA approved drug for ALS, riluzole, extends life on average by about two months,” says Abood. “Evidence from our study suggests that a marijuana-based therapy could create a much greater effect, perhaps extending life by three years or more.”
In the study, ALS mouse models were given either the marijuana compound THC, the marijuana compound cannabidiol, cannabidiol plus THC, or a placebo daily following the onset of disease signs. The researchers measured disease progression by testing how long the mice could stand on a slowly rotating rod. The more severe their nerve cell degeneration, the less time the mice can balance on the rod. In addition, two conditions of ALS, the loss of movement ability and survival time, were analyzed using a mathematical model.
“We found that treatment with THC delayed disease progression by seven days and extended survival by six days in the mouse model,” says Abood. “This corresponds to three years in human terms.”
Results also indicate that the combination of THC and cannabidiol further delays disease progression. Treatment with cannabidiol alone, however, had no effect.
Another part of the study determined that the marijuana compounds create their benefits by reducing two molecular processes, known as oxidative stress and glutamate excitotoxicity. These processes have been implicated in ALS and are thought to harm nerve cells.
As a next step, the researchers will further decipher the mechanisms of action of THC and cannabidiol.
Another animal study also indicates that a marijuana-like compound can protect brain cells from the damage produced by the disorder Parkinson's disease.
“For the first time, our research shows the neuroprotective value of marijuana-like compounds in a well-established animal model of Parkinson's disease,” says study author Andrea Giuffrida, PhD, of the University of Texas Health Science Center in San Antonio.
Parkinson's afflicts some 1 million Americans. Symptoms include slowness of movement, muscle stiffness, and shaky tremors, which can harm a person's ability to walk, talk, write, and eat. This havoc results from the death or injury of brain cells that produce the chemical dopamine.
“There are therapies that can help replenish depleted levels of dopamine and provide symptomatic relief, but none can reverse, prevent, or delay the progression of Parkinson's disease,” says Giuffrida. “Our research shows that marijuana-like compounds may be able to answer this need.”
In the study, researchers examined whether a marijuana-like compound designed to activate cannabinoid receptors, WIN 55212-2, could protect brain cells from degenerating in a Parkinson's mouse model, known as MPTP-treated mouse. These animals are given an injection of the toxin MPTP, which kills dopamine brain cells and induces symptoms seen in Parkinson's disease. The mice received a single injection of WIN 55212-2 30 minutes before the MPTP injection.
“We found that the brains of mice treated with the marijuana-like compound were almost indistinguishable from the brains of healthy mice,” says Giuffrida.
As a next step, the researchers are testing whether the marijuana-like compounds have neuroprotective value when brain cell damage is already present and whether they can prevent the progression of brain cell loss. “Learning more about the mechanisms by which marijuana-like compounds may slow down or prevent neurodegeneration in Parkinson's disease may translate into new pharmacological treatments that could fight this disorder in its earliest stages,” adds Giuffrida.
Another new animal study finds that drugs often prescribed for mild pain, like the pain from a tooth extraction, create greater pain relief when combined with a marijuana-like compound. If confirmed in humans, the combination strategy could be a boon to those with persistent pain conditions.
Persistent pain is notoriously difficult to treat. An estimated 50 million Americans endure some type of persistent pain that lasts for months, even years, including back pain, headaches, arthritis pain, and cancer pain.
“We found that the combination of a marijuana-like compound with either the mild pain medication ibuprofen or rofecoxib provides more pain relief than each of them given alone,” says study author Pierre Beaulieu, MD, PhD, of the University of Montreal in Canada .
The marijuana-like compound that researchers tested in the study is called anandamide, a natural internal chemical that activates the same system as marijuana. Nonsteroidal anti-inflammatory drugs such as ibuprofen and rofecoxib inhibit a specific enzyme that prevents the degradation of anandamide. This led researchers to suspect that supplements of anandamide could create even greater pain relief effects.
In the study, researchers injected the drugs into the back paw of rats. Then 15 minutes later, researchers injected the compound formalin into the same paw, which creates a persistent inflammatory pain condition locally.
“We found that compared to a separate administration of drugs, anandamide combined with either ibuprofen or rofecoxib doubled the animals' pain relief,” says Beaulieu. “Also since the compounds were injected locally, into the paw, we believe that the treatment would avoid some of the deleterious psychoactive effects seen with marijuana.”
Marijuana and marijuana-like compounds can act on receptors in the brain and the periphery, but only the brain ones contribute to the psychoactive effects.
As a next step, the researchers are testing the treatment strategy in animals that model a particularly hard-to-treat, persistent pain condition that can result from nerve injury, termed neuropathic pain.
Another new animal study supports the development of treatments that target the cannabinoid system for those with obesity. “We found that a compound that blocks activity in the cannabinoid system can significantly reduce food intake in animals by triggering activity in another system that is known to regulate appetite and body weight,” says study author Michael Cowley, PhD, of Oregon Health and Science University.
Obesity has risen at an epidemic rate during the past 20 years, according to the Centers for Disease Control and Prevention. More than 60 percent of adult Americans are overweight or obese. These people face an increased risk for a range of physical ailments, including high blood pressure, diabetes, and stroke.
“For many years anecdotal reports have described how marijuana use can increase appetite,” says Cowley. “Some users describe these cravings as the munchies.”
This and other work has prompted the development of drugs that combat appetite by blocking the cannabinoid receptors, which are activated by marijuana. “Some of these drugs are in late stage clinical trials,” says Cowley. “How they are able to control eating, however, has been a mystery.”
To shed some light on how they might work, Cowley and his colleagues gave mice a cannabinoid receptor blocker, termed AM251. “We found that the treated animals significantly reduced their food intake, as has been known for many years,” says Cowley. “We also found evidence that the activity of brain cells involved in the melanocortin system, which is known to control food intake and energy balance, increased.”
Several molecular measures signaled that there was increased activity in melanocortin brain cells. Included was the discovery that in treated animals there was a fourfold increase in the number of melanocortin brain cells that contained c-fos, a marker of cellular activation.
“These data show that cannabinoid receptor blockers can regulate the melanocortin pathways in animals and support the further development of cannabinoid blockers to help combat obesity in humans,” says Cowley.
https://www.sciencedaily.com/releases/2004/10/041027102621.htm