: minocycline, inflammation and glutamate.

[Guest guest]

,

I went to see my psycharist yesterday.

He knows about the spacy and sleepiness I complain about so much.

He told me something about inflammation and either glutamine or

glutamate.

I did a google on inflammation and glutamate and this article came

up.

My psycharist seems to think that increase inflammation must be

doing something to the increase glutamate in my brain.

After seeing some of this article below it looks like the

minocycline would do a double whamey on lyme.

I am going to check out this antibiotic like you suggested.

sandy

Minocycline

Disease Mechanism II: Inflammation

An Inhibitor of Inflammation, Free Radical Formation, and Protein

Aggregation

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Drug Summary: Studies have discovered that minocycline is able to

inhibit the activation of cells involved in inflammation as well as

decrease the production of free radicals. Because long-term

inflammation as well as increased free radical production are

believed to contribute to the progression of HD, minocycline

treatment may aid in delaying HD progression.

Minocycline and Inflammation

Minocycline, an antibiotic commonly used to treat acne and some

forms of arthritis, has been found to delay disease progression and

mortality in mice with Huntington's disease (HD). Minocycline is

able to cross the blood-brain barrier and exhibit anti-inflammatory

effects. The blood-brain barrier is a group of cells that form a

special, selectively permeable lining in the blood vessels of the

brain. This lining serves to prevent toxic substances in the blood

from entering the brain.

The anti-inflammatory effects of minocycline include inhibition of

microglial activation. Microglia are cells found in the brain that

are involved in the immune response. By inhibiting the activation of

microglia, minocycline inhibits inflammation. (For more on microglia

cells and HD, click here)

Minocycline and Free Radical Formation

In addition, minocycline has been found to decrease free radical

formation. Free radicals are very reactive molecules that are

capable of inducing various biological damage. Studies have reported

that free radicals play a role in the progression of HD. Minocycline

decreases free radical formation by inhibiting the production of

inducible nitric oxide synthetase (iNOS), an enzyme responsible for

the formation of nitric oxide (NO), which acts as a free radical in

the cell. Increased iNOS activity is present in activated glial

cells of the HD brain. As iNOS activity increases, more nitric oxide

molecules are produced, resulting in greater damage from free

radicals. Figure 1 shows an illustration of how minocycline

decreases free radical production.

Minocycline and Protein Aggregation

Minocycline also inhibits the production of caspases, a family of

enzymes involved in HD progression. Evidence suggests that caspases

are important mediators of inflammation and apoptosis. Caspases are

activated in the brains of humans with HD and certain mouse models

of HD. Once activated, caspases cleave the altered huntingtin

protein. Studies have shown that the cleaved huntingtin fragments

easily aggregate to form aggregations called neuronal inclusions

(NIs) that are toxic to the cell.

Caspases are also required for the processing of mature Interleukin-

1 (IL-1), one of the cytokines involved in the inflammatory

response. Cytokines are one of the " weapons " by which the immune

system removes and kills foreign substances. Mature cytokines such

as IL-1 then go on to initiate various pathways that further

increase cellular damage. By inhibiting caspases, minocycline could

potentially decrease formation of neuronal inclusions as well as

inflammation in the brain.

Because inflammation, free radicals, and neuronal inclusions are all

believed to contribute to the progression of HD, it is possible that

minocycline may work on these various pathways and decrease or delay

nerve cell death in people with HD. The success of minocycline as a

treatment for HD in animal models has not yet been applied to

clinical trials on humans, but pilot studies to test the

safety/tolerability and efficacy of minocycline in patients with

early HD are currently underway.

Research on Minocycline

Chen, et al. (2000) investigated the overall effects of minocycline

on HD progression. They hypothesized that minocycline should act on

the various disease mechanisms associated with HD and cause a delay

or improvement in the condition of treated mice.

To assess the efficacy of minocycline, the researchers looked at

changes in motor performance, survival rates, and amount of

huntingtin fragments and neuronal inclusions.

The investigators gave injections of minocycline to 6-week old mice

that expressed the symptoms of HD. At 6 weeks of age, the mice were

in the early stages of HD and showed some of the pathological

characteristics associated with HD, such as NI formation and

declined motor performance. The researchers found that minocycline

significantly delayed the decline in motor performance. Furthermore,

the treated mice lived 14% longer than untreated mice. This extended

period of survival is roughly equivalent to one to five years in

people with HD.

As a means of comparison with minocycline, the researchers also

injected tetracycline to another group of mice. Tetracycline is a

drug similar in effects to HD but is not known to cross the blood-

brain barrier. Mice treated with tetracycline showed no improvements

in performance or survival.

Minocycline-treated mice were also found to have significantly lower

levels of the huntingtin fragments. However, minocycline did not

inhibit formation of neuronal inclusions (NIs) despite the fact that

lower levels of huntingtin fragments are present in the brains of

minocycline-treated mice. (For more on neuronal inclusions, click

here)

These results indicate that minocycline-mediated neuroprotection is

not related to the effect that NIs have on the disease. The

researchers believe that NI formation is dependent on caspase

activation only during the initial stages of huntingtin aggregation.

Specifically, the cleavage of the full-length huntingtin may be the

caspase-dependent step. Once cleavage occurs, aggregation of the

fragments and consequent formation of NIs follows.

Once NIs begin to form, their growth is no longer dependent on

caspase activity since the formation of aggregates no longer require

caspase cleavage. In short, caspases produce the fragments needed to

form NIs but are not needed in the aggregation process of these

fragments. NIs have been detected in HD mice as early as three weeks

of age. The minocycline administered in this study probably did not

inhibit NI formation because it was administered when the mice were

already six weeks old. At that time, the early caspase-dependent

step was likely to have passed and aggregates were already able to

form without the need for caspase-activity.

Minocycline treatment also resulted in a 72% inhibition of iNOS

activity in brains of HD mice when compared to untreated HD mice.

These results indicate that neuroprotection from minocycline

treatment results in part from inhibition of iNOS activity, which

leads to decreased free-radical damage.

Researchers are not exactly sure how caspases are activated or

inhibited. They do know that caspases are not always present in the

cells and are produced only during specific times such as

inflammation or apoptosis. Beginning in the early stages of HD, the

altered huntingtin induces caspase production and activation,

resulting in mature IL-1 production and huntingtin cleavage. As

activated caspases play a role in HD progression, an effective

therapeutic intervention would require inhibition of these various

caspases.

Minocycline has been shown to inhibit caspase production, though the

mechanism by which inhibition occurs is still not known. Minocycline

also inhibits the formation of nitric oxide, making it an important

neuroprotective compound. Few side effects have been reported by

people treated with minocycline, as it is a fairly safe and common

antibiotic used to treat diseases such as acne and arthritis. With

the results of this study and its low toxicity, minocycline

represents a new potential therapeutic agent for HD treatment.

Tikka, et al. (2001) studied the effects of minocycline on

microglial proliferation due to NMDA receptor activation. (For more

on NMDA receptors, click here.) The researchers hypothesized that

minocycline treatment to cells exposed to excitatory molecules such

as NMDA can protect nerve cells from death.

NMDA receptors are activated by various excitatory molecules such as

NMDA and glutamate. Activation of these receptors leads to entry of

calcium ions (Ca2+) into the cell. Ca2+ entry then activates various

calcium-dependent proteins and molecules that can initiate

activities promoting cell death. The researchers believe that NMDA

receptor activation also leads to microglial proliferation and

activation of the inflammatory response. In the rat brain, the

microglia cells are known to have various NMDA receptors on their

surfaces, explaining why increased glutamate levels trigger

microglial proliferation and activation. Increased glutamate levels

or NMDA activation (as known to happen in HD cells) can therefore

induce microglial proliferation and activation.

Minocyline, a compound known to decrease the activation of

microglia, was used to study whether it will have any beneficial

effects on cells exposed to NMDA. To test the efficacy of

minocycline, the researchers looked at the amount of activated

microglia and the survival rates of nerve cells.

The researchers exposed a group of nerve cells to NMDA. They then

added minocycline to one group of nerve cells while left another

group untreated. Following NMDA administration, the researchers saw

an increase in microglial proliferation, followed by an increase in

nerve cell loss. These changes were also associated with increased

release of cytokines and nitric oxide free radicals. Minocycline

administration was found to reduce microglial proliferation and

nerve cell loss.

The researchers also discovered that increased microglial activation

enhances the neurotoxicity of NMDA. They believe that the enhanced

toxicity arose due to the increased release of cytokines and free

radicals from the activated microglia. Increased cytokine production

has been known to result in delayed removal of glutamate molecules,

enhancing NMDA receptor activation.

One way by which the researchers believe that minocycline was able

to reduce nerve cell loss was by its ability to inhibit caspases.

Because caspases are needed for the maturation of certain cytokines,

inhibiting the caspases could have decreased damage due to the

cytokines. Decreased production of the mature cytokines would have

enabled the normal removal of glutamate and excitatory molecules,

thereby decreasing NMDA receptor activation. However, the

researchers are still uncertain as to how minocycline was able to

reduce the proliferation of microglia.

In conclusion, the study showed that minocycline treatment results

in the inhibition of microglial activation and decreased release of

cytokines and certain free radicals. Minocycline may therefore be

beneficial to people with diseases such as HD that involve toxicity

due to excitatory molecules, although more research is needed.

-P. Chang, 5/6/03

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For further reading:

Chen, et al. " Minocycline Inhibits Caspase-1 and Caspase-3

Expression and Delays Mortality in a Transgenic Mouse Model of

Huntington Disease. " Nature Medicine. 2000; 6:797–801.

This study reported that minocycline was able to reduce huntingtin

fragments and nitric oxide formation, but had no effect on neuronal

inclusion formation.

Tikka, et al. " Minocycline Provides Neuroprotection Against N-Methyl-

D-aspartate Neurotoxicity by Inhibiting Microglia. " The Journal of

Immunology. 2001; 166: 7527-7533.

This study reported that minocycline treatment is associated with

reduced inflammation and nerve cell loss due to NMDA activation.

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Last Modified: 5-7-03

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Minocycline, I6

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You are HOPES site visitor no:

[Guest guest]

yes please do...is is very useful drug that does cross the bbb...

you need an llmd...

eric

irishdrought1955 <irishdrought1955@...> wrote:

,

I went to see my psycharist yesterday.

He knows about the spacy and sleepiness I complain about so much.

He told me something about inflammation and either glutamine or

glutamate.

I did a google on inflammation and glutamate and this article came

up.

My psycharist seems to think that increase inflammation must be

doing something to the increase glutamate in my brain.

After seeing some of this article below it looks like the

minocycline would do a double whamey on lyme.

I am going to check out this antibiotic like you suggested.

sandy

Minocycline

Disease Mechanism II: Inflammation

An Inhibitor of Inflammation, Free Radical Formation, and Protein

Aggregation