Able to move freely in 15 minutes!
 

Yes, that is the statement in the following report.
However, the bad news is they say "It is a long, long way to go before this will be tested in humans".
Ron


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Thursday, 8 February 2007, 00:12 GMT
Brain 'cannabis' Parkinson's hope
Boosting levels of the brain's natural cannabis-like chemicals could improve the treatment of Parkinson's disease, a US study suggests.
Mice with a similar condition could move normally within 15 minutes of having a cocktail including a compound which increases endocannabinoid levels.

But the scientists, writing in Nature, warned smoking cannabis would not have the same effect.

UK experts said the study increased understanding of Parkinson's.


"It is a long, long way to go before this will be tested in humans"
Dr Robert Malenka, Stanford University



Around one in 500 people in the UK have the disease.

It is a progressive, degenerative, neurological condition for which there is currently no cure.

Sufferers find increasing difficulty in moving their arms and legs. They develop tremors and facial tics, and gradually become more and more immobile.

Treatment combination

The researchers, from Stanford University Medical Center in California, focused on an area of the brain called the striatum which has already been linked to Parkinson's.

The activity of nerve cells in the striatum relies on the chemical dopamine.

If there is too little dopamine in that area, Parkinson's disease can develop.

They used mice genetically modified to have a condition like Parkinson's and marked certain cells with a fluorescent protein that glowed vivid green under a microscope.

Their study indicated that two types of cells formed a "push-pull system" in the brain - one is thought to be involved in activating motion, while the other is likely to stop unwanted movement.

If there is too little dopamine, it is thought that the cells which restrict motion become dominant, making it harder for a person to move.

An existing drug which boosts dopamine levels led to a small improvement in the animals' condition.

But it was only when they added an experimental drug designed to slow the breakdown of endocannabinoids, being developed by Californian firm Kadmus Pharmaceuticals, that the mice showed a dramatic improvement.

The mice went from being unable to move, to moving freely in 15 minutes.

'Greater insight'

Dr Robert Malenka, who led the study, said: "They were basically normal.

"This points to a potentially new kind of therapy for Parkinson's disease."

But he added: "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."

And he stressed that the study found the use of specific chemicals made the difference.

"That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

Kieran Breen, director of research and development at the UK's Parkinson's Disease Society, said: "The study provides us with a greater insight into how the nerve cells in the area of the brain affected in Parkinson's are connected and how they communicate with one another.

"A greater understanding of this will provide information about the changes that occur when nerve cells die and may ultimately lead to the identification of new targets in the cell at which drugs can act to treat the symptoms of the condition."



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Parkinson's therapy trial success (17 Oct 06 | Health )
Depression risk with Parkinson's (24 Jun 06 | Health )
Parkinson's Disease (13 Mar 03 | Medical notes )

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Anandamine
 

is the name given in an article I read in Nature in 1997 for what was thought to be the major active endocannabanoid. There are very small amounts of related compounds in chocolate, according to the same article. As I recall, the name is derived from the Indian (Sanskrit?) word for "bliss", pronounced [U]ananda[U].
Anandamine is a relatively simple derivative of a fatty acid and bears little structural similarity to THC, the main active ingredient in [I]Cannabis sativa.
I know nothing about the biosynthetic pathway for synthesis and breakdown of any of the endocannabanoids.
Robert

ZuchiniFlower/ Carolyn,
 

Hi both of you. My sincere apologies, I just found both of you have posted this story earlier. The BBC report was dated 8th Feb and I thought it was new. It is certainly interesting though, but frustrating it takes so long to develop.
Sorry again
Ron

Hi Ron ...
 

just to complete the postings thread I also posted it in "smoke and mirrors or smokin' dope".

Guess this topic generated interest, can't think why :)

Aftermathman.

P.S. Are you anywhere near Ivybridge ?

Ron...
 

One thing I noticed in RLSmi's post was that it is derived from a fatty acid. Since I had just posted regarding the purported value of essential fatty acids in the control of dyskinesias, that got me to wondering about the possible connections. Any thoughts from the chemistry involved?

-Rick

Intriguing...
 

From Wikipedia-

Anandamide: "The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine, which is itself made by transferring arachidonic acid from phosphatidylcholine (PC) to the free amine of phosphatidylethanolamine (PE).[6][7] Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of AA and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain. [8]"

Arachidonic acid: "Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids (especially phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositides) of membranes of the body's cells, and is abundant in the brain. It is a precursor in the production of eicosanoids: the prostaglandins, thromboxanes, prostacyclin and the leukotrienes (through enzymes including cyclooxygenase, lipoxygenase and peroxidase). The production of these derivatives, and their action in the body, are collectively known as the arachidonic acid cascade; see Essential fatty acid interactions for details.

Arachidonic acid is freed from phospholipid molecule by the enzyme phospholipase A2. It is also involved in cellular signaling as a second messenger.

Arachidonic acid is one of the essential fatty acids required by most mammals. Some mammals lack the ability to—or have a very limited capacity to—convert linoleic acid into arachidonic acid, making it an essential part of their diet. Since little or no arachidonic acid is found in plants, such animals are obligatory carnivores; the cat is a common example.[2][3] "

The Striatum...
 

is a "lower midbrain structure" into which afferent neurons from the substantia nigra and thalamus grow into. However , the striatum as we know it is the user of dopamine involved with mood instead of movement.
It all DOPE! Every antiparkinson medication that we take is supposed to "act' on "receptors" that induce functions according to how nature evolved to use them. Yes, stimulate receptors in the striatum and you'll feel better, trouble is it won't last and it will take ever increasing amounts of "Drug" to do it.
Once we've "used up" our dopamine pump, which is in two compartments, one governing movement, the other mood' more of it or something that elicits the same responses is needed. Cocaine is a powerful stimulator of the striatal dopamine pump, but just as with all other "mood" moderators, eventually you pay for its use.
Were dying guys and gals, just let us go out in bliss, cause the other way just ain't cuttin' the mustard; :( :( :( :(

I’ve been in interested in Arachidonic acid for awhile because I have taken COX-2 inhibitors which affect the Arachidonic acid pathway. It seems Arachidonic acid can be good and bad. It’s bad when it produces too many 'bad' prostoglandins and causes inflammation. And when it produces bad cytokines, as opposed to good ones. And when you inhibit COX-2, you upregulate LOX-5 which produces leukotrienes which can be bad (one kind causes asthma). It’s too complicated for me!

From the following article:

“cyclooxygenase-2-dependent arachidonic acid metabolites are essential in the development and maintenance of intestinal immune homeostasis.”

from:

Nature Medicine 5, 900 - 906 (1999)
doi:10.1038/11341
Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen
http://www.nature.com/nm/journal/v5/...m0899_900.html

***********

doi:10.1016/j.neuron.2005.12.004
Preview
Cannabinoids in Microglia: A New Trick for Immune Surveillance and Neuroprotection
Serge Rivest1, ,

Available online 4 January 2006.

From the article: “cytokine levels were either not changed (e.g., TNF-α) or moderately modified (e.g., IL-6) in the presence of endogenous and exogenous cannabinoids” which is good!

Microglia are the resident immune cells of the brain, and they are under permanent activity to patrol the cerebral microenvironment. A proper inhibitory feedback onto these cells is critical during both intact and injury conditions. In this issue of Neuron, Eljaschewitsch and colleagues report that such feedback is provided by the endogenous cannabinoid anandamine and CB1/2 receptor signaling, which ultimately leads to mitogen-activated protein kinase phosphatase-1 (MKP-1) induction. MKP-1 interferes with lipopolysaccharide-induced toll-like receptor 4 signaling and limits brain damage due to exaggerated microglial reactivity following acute NMDA injury.

http://www.sciencedirect.com/science...1e0b1cd9ba163b

More from the article:

In a series of very elegant studies, Eljaschewitsch and colleagues investigated the intracellular signaling pathways mediating the effects of AEA in BV-2 cells. They observed that the endogenous cannabinoids set microglia into a state of alert by a rapid MAPK phosphorylation and prevent overactivation in the presence of second stimulus. Indeed, MEK phosphorylation is reduced and Erk1/2 dephosphorylation takes place after AEA incubation in LPS-activated BV-2 cells. This is associated with a rapid induction of the mitogen-activated protein kinase-phosphatase 1 and 2 (MKP-1 and MKP-2). Here, MKP expression was not necessarily a direct consequence of the MAPK activation; although AEA alone can activate the MAPK, it switched off this pathway by rapidly upregulating MKP-1 induction following exposure to LPS. The combined treatment of LPS and AEA (not LPS and AEA alone) enhanced histone H3 phosphorylation on the MKP-1 gene sequence. Finally, these authors show that AEA was able to inhibit BV-2 cells in a CB1/2- and MKP-1-dependent manner and that MKP-1 can be found in microglial cells of MS patients. These data provide the first direct evidence that the CB receptors in microglia are coupled to Erk activation in regulating MKP-1 gene expression following histone H3 phosphorylation.

The authors reached the conclusion that the endocannabinoid AEA induces histone H3 phosphorylation, MKP-1 gene expression, and subsequent Erk1/2 dephosphorylation in activated (e.g., LPS) but not in resting microglia, which in turn abolishes NO release and finally leads to neuroprotection. It is however important to keep in mind that all of these studies were performed in culture systems where brain slices were exposed to BV-2 cells and in one occasion to primary cultures of microglia. Direct interaction of these immune cells with CNS tissues taken from another group of animals may not represent the real situation taking place in vivo. Exogenous microglia may be under a different state of immune activation, which may be quite different from endogenous cells behind the BBB. This may modify TLR4 expression, the affinity to its ligand, LPS signaling, and expression of a subset of genes. Also, how these exogenous microglia interfere with their endogenous counterparts still remains to be determined.

The role of microglial cells in neurodegenerative disorders remains a matter of great controversy and debate at the moment. It is clear that LPS-induced proinflammatory signaling in microglia is a natural response that is unlikely to be detrimental to neurons and other cells of the CNS. In contrast, a proper immune response may set the conditions for swiftly eliminating pathogens in cases of cerebral infection, phagocyting cell debris after injuries, and improving brain repair. Recent data support this concept, because inhibition of microglia and TNF-α production was found to cause more damages following acute excitotoxicity (Turrin and Rivest, 2006), delay in remyelination, and inhibit recruitment of progenitors (Arnett et al., 2001). Genes encoding innate immune proteins are induced not only by PAMPs, but also in response to brain injuries and during a variety of neurodegenerative disorders. What comes first (inflammation or cellular degeneration) remains largely unknown, and the role of such an innate immune/inflammatory response in the cerebral tissue has yet to be fully unraveled. It is clear that sustained and unregulated inflammatory reactions are detrimental to neurons, though the acute release of proinflammatory molecules may instead play a leading role in protecting neurons against invading pathogens and restoring homeostasis after the storm. The direction that the inflammatory response is taking and the appropriate inhibitory feedback on microglia may consequently be crucial for determining the ultimate outcome of these events in the CNS.

As shown by Eljaschewitsch and colleagues in this issue, cannabinoid receptor signaling and MKP-1 gene expression in microglia may well be the ultimate trick for allowing these cells to either protect or contribute to neurodegeneration following acute brain damage. Future experiments are nevertheless needed to specifically define the physiological relevance of such a system in the mature as well as developing brain in an in vivo context. Moreover, how cannabinoid receptors interact with TLR4 signaling in microglia remains to be determined. It is possible that such an interaction does not involve the classical LPS-TLR4-NF-κB pathway, but the MyD88-independent signal transduction system. Although AEA had very clear effects on NO release and iNOS gene expression in BV-2 cells, cytokine levels were either not changed (e.g., TNF-α) or moderately modified (e.g., IL-6) in the presence of endogenous and exogenous cannabinoids. This supports the MyD88-independent set of events and the subsequent IFN release, which is a key step for iNOS gene expression and NO biosynthesis (Schilling et al., 2002). As depicted by Figure 1, this pathway may be the direct target of the so-called inhibitory feedback of the AEA/CB1/2, Erk, and MKP-1 cascade. MKP-1 in causing Erk dephosphorylation and switching off MAPK would then lead to IFN gene repression. It is also tempting to propose a direct MKP-1/IRF interaction and dephosphorylation, such as in the case of Erk1/2. These events together are powerful novel mechanisms to prevent the production of type I IFNs and their costimulatory molecules (e.g., iNOS) without interfering with the MyD88-dependent signal transduction pathway and cytokine gene expression. Although still speculative at this point, these data open the door for a potentially new treatment to inhibit specific signaling events with no side effects on those that might have neuroprotective properties in microglia. Of interest is the fact that exogenous cannabinoids (e.g., marijuana) seem to improve recovery, decrease frequency in relapsing, and delay demyelination in MS patients. These frequently discussed beneficial assets of marijuana have to be validated with in-depth studies, but MyD88-independent pathways may well be the indirect target of cannabis through CB1/2 receptors and MKP-1 induction in macroglia and infiltrating macrophages. A new trick, yes indeed!

Anandamine is also called arachidonylethanolamide, if you're researching. :)

Nitric Oxcide Gas
 

Nitric Oxide Gas (aka Laughing Gas) kills neurons. John Hopkins has a Dr. Ted Dawson who studied Nitric oxide in neuronal injury in stroke and excitotoxicity and elucidated the molecular mechanisms by which nitric oxide and poly (ADP-ribose) polymerase kills neurons. His studies of nitric oxide led to major insights into the neurotransmitter functions of this gaseous messenger molecule. He co-discovered the neurotrophic properties on non-immunosuppressant immunophilin ligands.

Just adding more info to the mix.

Vicky

AND Arachidonyl Ethanol Amide = AEA (in case anyone was wondering)

Vicky
 

I'm pretty sure "laughing gas" is nitrous oxide, which is a very different compound from nitric oxide, the free radical compound made in normal metabolism by different forms of the NOS enzyme Nitric Oxide Synthase from the amino acid arginine.

One of the toxic effects of nitrous oxide is the destruction of methyl-cobalamine, the biologically active form of vitamin B12. B12 deficiency, as we all know, is very bad for neurons.

Robert

it still can kill neurons
 

One thing about nitrous aka laughing gas, though, is that it is normally mixed with oxygen Vicky. So, even though it isn't "nitric" your own history could still relate to your PD if you were forced to breathe it without proper oxygen. In fact, it is not rare for people to die from it when getting high if they wear a mask fixed to their head. They pass out from lack of oxygen and never wake up if there is no one there to remove the mask.

Nitric/nitrous oxide
 

RLSmi, You are correct, laughing gas is nitrous oxide, N2O, used by dentists as an anaesthetic. It is claimed to be safe, with no effect on the central nervous system.

http://www.ki.se/odont/cariologi_end...b/LJILJANA.PDF
Nitrous oxide sedation does not pose any significant negative effect on the CNS and
therefore can be used with common conditions such as:
-Cerebrovascular accident (stroke)
-Seizure disorder/fainting spells
-Parkinson’s disease

Nitric oxide, NO, is a very reactive compound which can do us harm.(and it opens the pores of the BBB!!)

Aftermathman,
Sorry to take so long to reply. No, I am nowhere near Ivybridge, I live in a small village called Selling, in Kent, about 8 miles from Canterbury.

Ron