Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin

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. Moreover, the endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous sytem). The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1β (interleukin-1β) 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, DAGLα (diacylglycerol lipase α) 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-1β 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.

CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release

Background: Endocannabinoids can affect pancreatic β cell physiology.

Results: Anandamide and 2-arachidonoylglycerol binding to CB1receptors induces focal adhesion kinase phosphorylation, which is a prerequisite of insulin release.

Conclusion: Focal adhesion kinase activation downstream from CB1receptors couples cytoskeletal reorganization to insulin release.

Significance: Identifies the molecular blueprint of 2-arachidonoylglycerol signaling in the endocrine pancreas, and outlines a kinase activation cascade linking endocannabinoid signals to insulin release.

Drugs that Block Cannabinoid Receptors Seem Problematic

One of marijuana’s best known side effects is hunger, and the discovery of the brain-cell receptor that mediates this effect has led to the development of nearly a dozen drugs meant to block it and thereby treat obesity. However, it is now clear that CB1, the cannabinoid receptor targeted by these therapies, is responsible for much more than “the munchies.”

On Oct. 2, the drug company Merck announced that its CB1-blocking drug taranabant had caused unacceptable side effects in a Phase III trial in obese patients. Merck has stopped development of the drug. The chief side effects of taranabant are anxiety and depression. Merck’s action follows the FDA’s rejection in 2007, essentially for the same reasons, of Sanofi’s CB1-blocking drug rimonabant (brand name Acomplia).

“I was hoping that taranabant would do better than rimonabant, but I am not really surprised that it didn’t,” says Daniele Piomelli, a researcher at the University of California, Irvine, who has been in the forefront of research in this area. “It seems that the endogenous cannabinoid system is an important regulator of the stress-coping mechanism engaged in anxiety and depression.”

The CB1 receptor
Aside from being marijuana’s prime target, CB1 is one of the most widely expressed receptors on cells throughout the body, and it is particularly abundant in the brain. The receptor appears to have somewhat different functions in each organ system. In the brain, the binding of CB1 by its corresponding neurotransmitters, or “ligands,” also has multiple effects.

On the whole, however, CB1’s job seems to be to modulate the activity of other systems in the brain. Typically CB1 receptors stud the terminals of a neuronal output stalk, or axon, which delivers signals to another neuron across a synapse. Greater activity in the synapse tends to produce a buildup of the brain’s own cannabinoids, which bind to CB1, which in turn triggers a reduction in the flow of signals across the synapse.

Some evidence suggests, for example, that this braking or calming effect of the CB1 system is necessary to prevent the uncontrolled neuronal activity known as epilepsy. Lab tests with neuronal cultures made prone to seizure-like activity have shown that the blockade of CB1 leads to continuous firing, which stops when the blockade is lifted.

As evidence from marijuana users suggests, CB1 activation also tends to counteract the brain systems that produce anxiety, depression and pain. In one experiment in 2002, mice bred without the gene for CB1 and conditioned to associate a certain sound with pain were significantly less able to forget the fearful association than were normal mice. “Mutant mice lacking CB1 receptors are known to break down more easily when stressed, while drugs that boost endogenous cannabinoid activity strengthen the ability of animals to cope with stress,” Piomelli says.

The recent clinical trials of rimonabant and taranabant, both of which bind to CB1 in a way that reduces its activity, amount to large-scale tests of CB1’s function in humans. Both sets of trials indicate that blocking CB1 activity in humans produces harmful effects like those seen in animal experiments.

When an FDA panel unanimously rejected Sanofi’s application for rimonabant in 2007, it cited sharply increased rates of anxiety, depression, suicidal thoughts and mood disorders in patients taking the drug.

Although rimonabant was approved by the European Medicines Agency in 2006, a meta-analysis of clinical trial data, published in the Lancet in 2007, determined that people taking the drug, as opposed to a placebo, were two to three times more likely to stop taking it because of depression or anxiety. This was despite the fact that people reporting a depressed mood were not allowed into the trials.

“They have to exclude individuals with mood disorders in such studies because they don’t want the liability issues, and it enables a cleaner interpretation of the trial data,” explains Richard Deyo, a pharmacologist and cannabinoid expert at Winona State University in Minnesota. But to understand the full potential impact of side effects, he adds, “you’d have to look at the whole population.”

Better to boost CB1 than to block it?
Several other drug companies have CB1 blockers in early clinical trials, though the failure of rimonabant and taranabant casts a cloud over their further development.

Other academic and commercial researchers have sought not to block CB1 activity but to boost it, to relieve depression and anxiety. But this strategy, too, is fraught with complications.

The most obvious problem is that the CB1-binding molecule known as THC is potentially addictive, as are other cannabinoid molecules that directly bind and activate CB1. CB1 also appears to have different effects depending on which system it is modulating.

CB1 receptors are found on two broad classes of nerve terminals: excitatory, which increase the activity of target neurons; and inhibitory, which reduce activity, Piomelli says. CB1 therefore can either “put on the brakes” or “release the brakes” depending on which of these systems it modulates.

Any strategy that floods the brain with CB1-binding molecules will thus have a host of effects, depending on the systems affected, the dose that reaches each system, and the ongoing level of activity in those systems—which in turn can vary according to mood, personality and genetic differences in brain chemistry.

For example, at low to moderate levels, THC, which is the main active ingredient in marijuana, appears to have reliable pain- and anxiety-relieving effects, Deyo says. “As you increase the dose, though, you get memory blocking effects, you get a tendency towards depression and you also get the potential for hallucinations,” he adds. Furthermore, THC’s effects appear to vary according to gender.

The ‘make more of it where it’s needed’ strategy
To get past such obstacles, Piomelli and his colleagues at UC-Irvine recently devised an indirect CB1-activity boosting strategy, similar to that used for some other brain-cell receptors. The body’s main CB1-activating molecule, anandamide, is normally broken down quickly by enzymes near the synapses where it works. Piomelli reasoned that by preventing this continual degradation of anandamide, he could keep it more of it around synapses and thus maintain a higher level of CB1 activity. In this way he could also increase CB1 activity primarily where it was already occurring and needed, and to a lesser extent in other areas of the brain and body where the boosting of such activity could produce undesired side effects.

In a paper published in the journal Biological Psychiatry on Sept. 22, Piomelli and colleagues, together with a National Institutes of Health team led by Stephen Goldberg, reported on a set of experiments using this strategy in monkeys. Administering a drug that inhibits FAAH, an anandamide-eating enzyme, the researchers soon were able to measure higher levels of anandamide in the monkeys’ brains.

Using standard tests, they found that this approach did not reinforce other drug-taking behavior, as THC normally does. “Our results,” the researchers wrote, “suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.”

Piomelli explains that when the FAAH inhibitor, currently named URB597, is administered, anandamide levels rise and appear to reduce inhibitory controls on a midbrain region where neurons pump out the neurotransmitters serotonin and noradrenaline. The effect is to boost the levels of these neurotransmitters in the brain.

“This physiological effect is similar to that produced by certain antidepressant drugs,” says Piomelli, “and indeed URB597 displays profound antidepressant-like properties in rats and mice.”

Organon, a unit of pharmaceutical company Schering Plough, holds the rights to URB597 and is considering clinical trials of the drug for pain relief.

HOGGIN THE BRIDGE 2012

What a fantastic day this years Hoggin’ the Bridge turned out to be.

Motorcycles lined up for the Hoggin the Bridge event

I understand there were about 2000 bikes there this year, this was less than previous years but still a fantastic turnout. The weather was dry albeit a bit foggy, however there were a few sunny spells and it wasn’t too cold.

I went with a friend who has a Honda Shadow. She has never been on a bike run of more than 2 bikes before and she was very impressed. I could see her grin in my rear view mirror all day. Apparently in Cardiff on her way to my house, some biker pulled up alongside her at the lights and asked if she was going hoggin’. He told her the third lot of bikes leaving the services was the safest to be in as the others tended to get a bit scary and competitive with riders jostling for space. I have never found this to be the case but we waited until near the end to leave the services. As soon as we set off on the run we went over the Severn bridge. It was a bit foggy and as the second ‘H’ bridge support appeared through the fog I realised all I could see in front of me were bikes and all I could see in my rear view mirror were bikes.

At one point a huge articulated lorry appeared in the middle of the sea of bikers. It reminded me somewhat of those nature programmes when a colony of ants have found a dead animal, much larger than they are, and between them they carry it back to their nest. The lorry looked – well – awkward.

As in other years lots of families had turned up to see the bikes. Lots of kids were standing by the roadside thrilled to be able to give some of the bikers ‘Hi-5′s’ as they went past. I spotted a few old folk having been parked outside their houses in their wheelchairs with a blanket over their legs. They were waving enthusiastically at us as we went past. Banners had been made advising ‘Honk if you’re Hoggin”. We all did!

Homemade Motorcycle Brake Lights

As a motorcyclist, visibility is paramount to the safety of the rider. With this in mind, Pete Mills wired up his own super-bright brake light assembly using bright red LEDs. Not only are the lights powered by the onboard electrical system, but they can be toggled to either stay solid, or blink depending on the rider’s choice. This was done using an ATTiny85 microcontroller.

LED Motorcycle Tail Light
Vegetable Oil-Powered Motorcycle Interview
Motorcycle Control Panel with Arduino

Domestic Drama Lands Laughing Devils “Sandman” In Jail

Mister Sandman, bring me a dream.
Make her the cutest that I’ve ever seen.
Give her two lips like roses in clover.
Then tell her that her lonesome nights are over.

It’s ironic how this song, which was most notable in the movie “Back To The Future“, mimics the reality behind the reality TV show called The Devils Ride.

I’m referring to Robert Joseph “Sandman” Johnston, a member of the Laughing Devils MC and one of the more popular characters on the reality TV series. He was arrested for attempted murder after allegedly stabbing a man during a burglary just prior to Christmas.

Mister Sandman’s Melis
Mister Sandman’s Melis
There is some speculation (HERE) that Mister Sandman wanted to surprise his ex-wife? — SATIRE ALERT — with a belated Christmas gift. After realizing that he’d misplaced the house keys he let himself in and then discovered another man in the bedroom, and became concerned… came to her defense by stabbing the “assailant” three times in the back. The police somehow misunderstood his good intentions.

I’m sure the show producers are salivating over all the possible plot twists for a second season. This is all just another sad chapter of reality TV – salacious, exploitative, celebratory violence, abusive and predatory behavior – not to mention an extraordinarily colorful life of a motorcycle club member. Not only do we have to turn the channel to avoid the “vast wasteland” called The Devils Ride, we have to endure nit wits like Kim Kardashian and Jessica Simpson, uneducated goofs who are followed around, their every activity plastered on magazines and online, who’ve got nothing to say. They’re not entertainers, and to keep it real there isn’t much reality in reality TV.

And before you fire-up the keyboard to tell me that I don’t get The Devils Ride or am stupid or there is something inferior about me or I’m just not as far out there on the motorcycle outlaw frontier as Sandman is… Keep in mind that The Devils Ride is the creation of the Santa Monica production company Bischoff-Hervey Entertainment and that show producer, Eric Bischoff is the author of the acclaimed memoir Controversy Creates Cash.

There are a number of things I am looking forward to in 2013 and high on that list is that The Devils Ride implodes and gets cancelled.

Previous posts: Laughing At The Laughing Devils; Laffing Devils Are The New World Order; The Laughing Devil Tickle Monster;

Robert Joseph “Sandman” Johnston photo courtesy of Discovery Channel. Melis photo courtesy of Twitter page.

New Honda CB Shine 125 cc Specifications Review Price Mileage Cost Models Power Colors

New Honda CB Shine bikes in different variants with colors and other options.

New Honda CB Shine 2012 125 cc Specifications Review Price Mileage Cost Models Power Color

NewHonda Shine Kick Drum Spoke Bike Mileage is 55-60 KMPL in city and 60-65 on highways KMPL.

NewHonda Shine Self Drum Alloy Bike Mileage is 55-60 KMPL in city and 60-65 on highways KMPL.

NewHonda Shine Self Disc Alloy Bike Mileage is 55-60 KMPL in city and 60-65 on highways KMPL.

NewHonda Shine Kick Drum Spoke Bike Price at Ex-showroom is Rs 50,301 and On Road price is Rs 58,359.

NewHonda Shine Self Drum Alloy Bike Price at Ex-showroom is Rs 53,955 and On Road price is Rs 62,540.

NewHonda Shine Self Disc Alloy Bike Cost at Ex-showroom is Rs 57,082 and On Road price is Rs 66,118.

NewHonda CB Shine Bike 125 cc Specifications :

Engine: Air cooled SI engine, 4 stroke engine
Displacement: 124.7 CC
Power: 10.12 bhp at 7500 rpm
Torque: 10.54 Nm at 5500 rpm
Ignition: Digital CDI
Battery: 12V maintenance free Tough frame
Cluth : Manual Clutch Wet Multi Plate
Stroke : 55.2
Wheels: Alloy
Brake: Front Disc, Rear Drum
Tyres: Tubeless tyres with optional Tuff up tubes
Weight: 120 Kilograms
Tank / Fuel Capacity: 10.5 liters

Honda CB Shine 125 cc Bike Colors Availabe :

Force Silver Metallic
Black
Geny Grey Metallic
Rebel Red Metallic
Monsoon Grey Metallic

Honda CB Shine 125 cc Bike Pros :

Tubless Tyre.
Stylish Looks.
Optimax Engine.

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