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Progesterone as Emergency Tx for TBI

TBI = traumatic brain injury
--1.5 to 2 million people in the U.S. sustain a TBI each year
--TBI causes 50,000 deaths and 80,000 new cases of long-term disability per year in US
--major cause of death and disability among children and military personnel.
--one article said no new medicines or therapies for TBA have come to light in over 30 years (I doubt this)
--it occurs to me to wonder if we gave progesterone prophylactically to boxers and football players, would they keep playing and retain more smarts? or would they quit? it hasn't been studied yet. =-]



WHAT i HEARD ON NPR
--Dr Stein was interviewed on NPR, PhD from Emory University in Atlanta, Georgia
--Stein is director of Dept of Emergency Medicine's Brain Research Lab
--Stein said on the radio that women heal better from TBI than men, and that is what got them started playing with progesterone as a possible treatment
--progesterone is also a neurosteroid that exerts protective effects on human tissue
--one theory about why prog levels are so high in pregnancy is that it is needed to protect the developing fetus
--the process of development and the process of healing from injury have things in common
--lead researcher Dr. David W. Wright, MD
--research in collaboration with the laboratory of Dennis Liotta, PhD, Emory prof of chemistry
--studied in animal models extensively (15+ years) with good outcomes
--now experimenting on humans
--another researcher: Asa G. Candler Professor of Emergency Medicine at Emory School of Medicine

PILOT STUDY ON HUMANS
--published in the October 2006 issue of the Annals of Emergency Medicine.
--the science so far shows a reduction in death rates by 50% compared to placebo
--also found substantial reduction in disability after injury, improvement of functional outcome
in pts with moderate brain injury
--the pilot study was small: 77 pts got the progesterone, 23 didn't
--level 1 trauma center
--pts experienced "blunt" traumatic brain injury usudt MVA, motocycle crash, fall
--average time after injury that tx was initiated: 5.9 hours
--longest time period after injury included in study: 11 hours
--twas funded by the National Institute of Neurological Disorders and Stroke
--3-year, randomized, double-blind, placebo-controlled phase 2 trial
--"Progesterone for the Traumatic Brain Injury — Experimental Clinical Treatment (ProTECT)"
--gave IV prog over 3 days to brain injured pts
--there were no adverse events associated with giving prog (to both men and women)
--progesterone reduces edema, prevents neuronal loss
--pts had a postresuscitation Glasgow Coma Scale (GCS) score of 4 to 12
--enrolled with proxy consent
--at 30 days postinjury, the death rate in prog group = 13% compared with 30% for placebo
--no difference in adverse event rate
--functional outcomes measured via Disability Rating Scale and Glasgow Outcome Scale
--IV progesterone never used before for TBI, used twice before in other clinical areas
--what areas???
--now known that TBI damage mostly occurs after initial injury dt cytotoxic secondary cascade
--this damage can continue for up to a year

HOW PROGESTERONE WORKS
--preclinical studies suggest prog may stop progressive damage by:
----modulating excitotoxicity
----reconstituting the blood-brain barrier
----reducing cerebral edema
----downregulating the inflammatory cytokine cascade
----decreasing apoptosis
----enhancing recovery from cortical, cerebral, and spinal cord injury

NEW STUDY IN THE WORKS
--ProTECT III begins early next year
--large, multicenter phase 3 clinical trial of 1000 human patients
--also animal studies: blast-related injury, a major cause of disability among soldiers
--will also look at peds
--currently TBI is the leading cause of death due to injury among US children

OTHER STUDY IDEAS
--may limit damage from transient and permanent ischemic stroke
--hoping to start a study that targets this population

MAKING WATER SOLUBLE VERSIONS OF PROGESTERONE
--one abstract reports on prog analogues that are more water-soluble
--lack of water solubility limits delivery of prog, must be prepared hours ahead and cannot be kept at room temp
--two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of TBI

COMBINING PROG WITH VITAMIN D
--second abstract
--there's evidence that adding vitamin D to progesterone enhances the hormone's effectiveness
--they gave this to neurons under stress in the laboratory
--vitamin D is a steroid hormone, inexpensive, safe, and active via many mechanisms
--a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death

WHAT IS EXCITOTOXICITY? GLUTAMATE OVERLOAD!
==pathological process by which nerve cells are damaged and killed by glutamate etc
--occurs when glutmate receptors (ie NMDA and AMPA receptor) are overactivated
--glutamate is the major excitatory neurotransmitter in the mammalian CNS
--glutamate is an amino acid
--excitotoxins like NMDA and kainic acid which bind to these receptors
--levels of glutamate can be pathologically high without those chemicals
MECHANISM
--excitotoxicity occurs when high levels Ca2+ enter the cell
--Ca2+ influx-->activates enzymes incl phospholipases, endonucleases, proteases such as calpain
--these enzymes damage cell structures
--it occurs to me that an influx of Ca2+ ions is one of the signals in the apoptosis cascade
--excess Ca2+ in cytosol-->mitochondrial permeability transition pore opens
-->mito releases enzymes-->apoptosis
--open pore can also cause mitochondria to release more calcium
--production of adenosine triphosphate (ATP) may be stopped
--ATP synthase may in fact begin hydrolysing ATP instead of producing it
--inadequate ATP production-->loose electrochemical ion gradients
--glutamate transporters require ion gradients to remove glutamate from ECM
--so glutamate uptake stops, or the transporters actually reverse, dumping more glutamate and aspartate into ECM
--there's another mechanism that induces apoptosis but my brain is fried
CAUSES
--may occur dt spinal cord injury, stroke, TBI and neurodegenerative dz of CNS, ex: MS, Alzheimer's, ALS, Parkinson's, alcoholism or withdrawal, Huntington's
--other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia and status epilepticus


HISTORY OF GLUTAMATE RESEARCH
--negative effects of glutamate first observed in 1954 by T. Hayashi
--Hayashi, a Japanese scientist, applied glutamate directly on CNS causing siezure activity
--this report unnoticed for several years
--don't know whose brain he put glutamate on
--GLUTAMATE IS IN MSG and NUTRASWEET
(this is msg, below)

--D. R. Lucas and J. P. Newhouse, 1957 fed MSG to newborn mice
-->destroyed the neurons in the inner layers of the retina
--1969, John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the brain and coined the term excitotoxicity
--also assessed that cell death was restricted to postsynaptic neurons
--glutamate agonists were as neurotoxic as glutamate
--glutamate antagonists could stop the neurotoxicity
--???so I guess progesterone is a glutamate antagonist???
--is this why it makes people sleepy?
--in normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds
--when glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by apoptosis
--this happens after TBI: the ischemic cascade
--ischemia-->high glutamate, high aspartate accumulations in ECM-->apoptosis
--low O2, low glucose worse then situation
--tx: deep chemical coma mmb induced in pts w/ TBI to reduce metabolic rate of the brain
--main goal of coma inductoin: reduce ICP

--NUTRASWEET / ASPARTAME is rapidly metabolized into glutamate and aspartate
--some debate as to how much you must take in to cause plasma levels to spike
--also don't know if it crosses the BBB
--glutamate doesn't normally cross the BBB in most parts of the brain without transporter uptake
--serum glutamate concentrations usu higher than in ECM of brain
--worry re: parts of brain not protected by BBB (which are these???)
--soy lecithin, nutritional yeast, and yeast extract are listed at bottom of wiki article on neurotoxicity, do these have glutamate in them???

SOURCES
http://www.medscape.com/viewarticle/545573
http://www.sciencedaily.com/releases/2009/10/091019122636.htm
http://www.news-medical.net/news/2006/10/03/20369.aspx
http://en.wikipedia.org/wiki/Excitotoxicity

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