> In article <kofi-C3FEF6.14043508102003 at news03.west.earthlink.net>,
> kofi <kofi at anon.un> wrote:
>> > If someone with some form of TMJ, attention deficit or glutamate
> > excitotoxicity experienced a severe worsening of symptoms when taking a
> > 5AR inhibitor, would you attribute that then to some neurological
> > function performed by 5AR itself?
>> It's not a 5AR inhibitor - it's a competitive inert substrate. That is
> to say it attenuates the 5-alpha-reduction process needed to convert the
> inactive to the neurologically active steroid. So I would attribute
> that to changes in active steroid levels, but I think they would need to
> be gross before it would be allowed to produce enough disruption to
> seize.
I thank you for your reply, but it's left me with still more questions.
What exactly is going on with drugs like dutasteride and finasteride? I
thought they blocked one or more isoforms of 5AR from converting
testosterone to DHT and progesterone to allopregnanolone? Can you
describe their method of action more into layman's terms? I've
consulted with two practicing neurologists and was underwhelmed at their
lack of knowledge.
Isn't progesterone itself classifiable as a "neurologically active
steroid?"
>> I'm not at all sure what you mean by grouping "TMJ, attention deficit or
> glutamate excitotoxicity" there - I don't know what TMJ is, aside from
> the temporo-mandibular joint; I know of no link between ADD and
> glutamate or GABA modulation; and "glutamate excitotoxicity" refers to
> cell death triggered during brain ischaemia as far as I know. Why do
> you specifically refer to these as if they were at particular risk for
> finasteride side effects?
Not everything that's vulnerable to seizure lies is in the brain. TMJ
pain/myofascial pain is, frankly, not well understood. Many doctors
don't even know it exists and a definition of it wasn't agreed upon
until quite recently. It's common in women and seems to relate to
progesterone swings, quite possibly as much due to its effects on joints
and collagen than on GABAergic function; I don't know. It seems to
create trigger points - loci of anatomical stress involving bundles of
nerve, tendon, muscular and vascular tissue which knot up painfully (and
can create some ischemia). Lidocaine injections - which can bind to
GABA receptors - are used as treatments. Glutamate injections into rat
masseters can induce TMJ pain. Trigger points have been experimentally
induced with intramuscular injections of bradykinin, histamine, 5-HT,
PGE2 and ATP. TMJ is known to advance into Parkinson's in severe cases
and GABAergic drugs have had limited recent success treating Parkinson's
and have long been used in TMJ - although since the associated nerves
lie outside the blood-brain barrier, it doesn't seem to have occurred to
anyone that GABA per se or a combination of precursor amino acids might
serve the same purpose. Since no one knows what causes myofascial pain,
I can't explain the exact role GABA transmission plays or what problem
5AR blockers might pose. From my own experience, I can say they are a
problem.
Mercury poisoning increases glutamate in certain nerves. Mercury
poisoning and autism have overlapping symptoms (see
<http://www.autism.org/ari/mercurylong.html>). I can't draw a direct
link between autism, ADHD and glutamate excitotoxicity except to note
that many clinicians find GABAergic supplements like glutamine and
L-Theanine helpful (see <http://www.dietsexercise.com>). Many people
with TMJ pain complain of symptoms similar to ADHD and benefit from some
of the same guidelines.
I can even link intestinal candidiasis/leaky gut syndrome too; it
impairs glutamine absorption. Both LGS sufferers and TMJ patients seem
prone to frequent sinus infections whose underlying cause is candida
albicans, not bacteria. Administering antibiotics makes the short term
problem better and the long term problem worse - especially when more
gut colonies of lactobacillus die off. Both LGS and TMJ can feature
sleep disturbances/insomnia, impaired memory, emotional control problems
and other issues. I posted a question about progesterone replacement on
a candidiasis list and got some interesting feedback. Some of the women
even had TMJ problems. Of course, it's all a lot more complex than just
inhibition. (Blame GABA. Sounds like a new _Southpark_ song poking fun
at '70s supergroups, doesn't it?)
I have no doubt you would not expect to see side effects from low-dose
5AR inhibitors on most people. However, there are these disorders
involving GABAergic signaling - sometimes only in small areas outside
the brain - which can be affected (from my own experience it takes a few
days or weeks to build). Who knows? All of these disorders involve
disturbed sleep patterns. Testosterone supplementation can create sleep
disturbances. 5AR inhibition can increase testosterone levels by 20-30%
although you would expect general androgen-related stimulation to drop
since DHT has a greater affinity for the androgen receptor. Maybe
there's something funny going on there? My first suspicion is with GABA
function, although maybe THDOC is the culprit. There are plenty of 5AR
deficient males. While they don't get prostate cancer or go bald, I'm
not aware of any deficiencies in GABAergic signaling. Maybe they've got
another pathway to take up the slack (3alpha-HSD?). Maybe there's some
other direct function of 5ARs in the nervous system people have missed.
The whole thing confuses me and I'm simply trying to sort it out.
It's of particular interest because the other baldness drug, minoxidil,
can have effects on GABA too. It increases intracellular calcium which
can induce NMDA-type glutamate receptors to suppress GABA function. It
comes with a generic warning not to use it if you have ringing in your
ears (glutamate, perhaps?). Of particular worry for sufferers of TMJ,
minoxidil upregulates VEGF - arguably the worst angiogenic factor you
can use to replace ephrin (baldness is a form of osteoporosis which
occurs when an overactivated androgen receptor produces too much TGF-B
and somehow knocks out ephrin and BMP-7 expression). As a form of
arthritis, TMJ pain is sustained, in part, by VEGF overexpression. The
joint pain disturbs sleep and nearby nerves, etc., etc.
While I have you here, can you comment on the impact of insulin
resistance and/or proteasome inhibition on GABA receptor function?
Insulin resistance increases with age and certain forms of TMJ are more
common among diabetics. I'm looking at proteasome inhibition to pump up
some bone morphogenic proteins but I'm concerned about secondary effects.
>> I have communicated with people who took even low dose finasteride
and
> > experienced, consistently, very palpable differences in the way they
> > felt while drinking.
>> I can certainly believe this - both substances act at the GABA-A
> receptor, and the phenomenon of being drunk shows just how little the
> system needs to be perturbed in order to feel very weird indeed. If
> you're simultaneously altering the levels of another substance acting at
> the same receptor, I would expect strong subjective differences in the
> experience. Alcohol and allopregnanolone would interact differentially
> depending on the subunit composition of the receptor itself (i.e. the
> different variants of the elements forming the channel). In that case,
> changing both factors simultaneously would have different effects in
> different parts of the brain (e.g. synergistic inhibition in one region,
> partial antagonism in others) and would alter the sensation hugely I
> think.
Can you explain how finasteride acts at GABA(A)? I thought it merely
affected it through allopregnanolone/thDOC synthesis? I'm also curious
how alcohol affects GABA. Does ethanol bind directly? It's always
given me headaches. The only research I've been able to find indicates
it lowers the threshold of Substance P release from vanilloid receptors
- another substance not to mix with TMJ. I had thought it acted through
this avenue to aggravate neuralgia. (Also had some strange ups and
downs on DHEA, but I won't go into it.)
> An interesting conversation - why are your posts anonymous, by the way?
I post in less friendly places on the internet sometimes frequented by
your more irritable, obsessive-compulsive personalities - hence my
interest in inhibition.
What's the weather like in Newcastle this time of year? Warming up, I'd
imagine? I had a roommate from there when I was studying at Sydney Uni.
