doi:10.1016/j.eurpsy.2008.06.001
Copyright © 2008 Elsevier Masson SAS All rights reserved.

http://tinyurl.com/684hut

Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: A comparative post-mortem study

Tanja M. Michela, b, c, , , Sophia Frangoub, c, Sibylle Camarad, Dorothea Thiemeyerd, Julia Jecelg, Thomas Tatschnere, Robert Zoechlingf and Edna Grünblattd


Abstract
Introduction
A growing body of evidence suggests that the glial cell line-derived neurotrophic factor (GDNF) is involved in the aetiopathology of mood disorders. GDNF is a neurotrophic factor from the transforming growth factor-β-family, playing a role in cell development and function in the limbic system. This is the first study to examine GDNF concentration in different brain regions of patients with depressive disorder (DD).

Material and Methods
We used sandwich-ELISA-technique to ascertain GDNF concentration and Lowry assay for overall protein levels in post-mortem brain tissue of 7 patients with recurrent depressive disorder and 14 individuals without any neurological or psychiatric diagnoses. We included cortical regions as well as limbic area's (hippocampus, entorhinal cortex) basal ganglia (putamen, caudate nucleus), thalamus and cingulated gyrus.

Results
We found a significant increase in GDNF concentration in the parietal cortex of patients with DD compared to the control group. In other regions the trend of an increased GDNF concentration did not reach statistical difference.

Discussion
This proof of concept study supports previous findings of an alteration of the GDNF in patients with depressive disorder. However, for the first time a significant increase of GDNF in a cortical brain area was found in DD.

BRAIN -derived neurotrophic factor (BDNF) is a neurotrophic factor found in the brain and the periphery. It is a protein that acts on certain neurons of the central nervous system and the peripheral nervous system that helps to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after nerve growth factor (NGF) and neurotrophin three (NT-3).

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.

Despite its name, BDNF is actually found in a range of tissue and cell types, not just in the brain. It is also expressed in the retina, the CNS, motor neurons, the kidneys, and the prostate.


Effects of stress and BDNF's link in depression
Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and leads to an eventual atrophy of the hippocampus if exposure is persistent. Similar atrophy has been shown to take place in humans suffering from chronic depression. In addition, rats bred to be heterozygous for BDNF, therefore reducing its expression, have been observed to exhibit similar hippocampal atrophy, suggesting that an etiological link between the development of depressive illness and regulation of BDNF exists. On the other hand, the excitatory neurotransmitter glutamate, voluntary exercise, caloric restriction, intellectual stimulation, and various treatments for depression (such as antidepressants and electroconvulsive therapy) strongly increase expression of BDNF in the brain, and have been shown to protect against this atrophy.


Mechanism of action for BDNF
BDNF binds at least two receptors on the surface of cells which are capable of responding to this growth factor, TrkB (pronounced "Track B") and the LNGFR (for "low affinity nerve growth factor receptor", also known as p75).

TrkB is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkB mediates the effects of BDNF and NT-4,TrkA binds and is activated by NGF, and TrkC binds and is activated by NT-3. NT-3 binds to TrkA and TrkB as well, but with less affinity.

The other BDNF receptor, the LNGFR, plays a somewhat less clear role. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity - since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that the LNGFR may signal a cell to die via apoptosis - so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.


Other diseases associated with low BDNF levels
Various studies have shown possible links
http://www.answers.com/BDNF?afid=TBarLookup&nafid=27

stress - over adrenaline activation - burn out of the mind -

the area of the brain -I believe the caustic area where spiral down begins is -

not in the substantia nigra -
I feel strongly PD - starts in the adrenal medulla -

World of the Body: adrenal glands
There are two adrenal glands, one sitting on top of each of the kidneys. They are pyramidal in shape and weigh about 4 g each. Their presence was recognized as early as the late sixteenth century, but it was not until 1805 that Cuvier reported that the adrenal was made up of two regions, the cortex on the outside and an inner medulla. Fifty years later, a Guy's Hospital physician, Thomas Addison, showed that the adrenal glands were necessary for life, by identifying them as the site of damage in a previously mysterious and ultimately fatal illness, which became known as Addison's disease.

The adrenal cortex

is known now to have three distinct regions: the zona glomerulosa, zone fasciculata, and zona reticularis. The first of these regions produces the steroid aldosterone, while another steroid hormone, cortisol, is produced by the other two regions. The cells which make up all of these regions are full of lipid droplets containing cholesterol, which can be converted into the steroid hormones.


The adrenal medulla

makes up about 10% of the substance of the adrenal glands and is essentially and developmentally a part of the sympathetic division of the autonomic nervous system. It consists of ‘chromaffin cells’ (so named because of their affinity for chromium) and their main product is adrenaline (also known as epinephrine), which is involved in the fight or flight reaction along with cortisol. More adrenaline is produced in times of stress, by the stimulating action of sympathetic nerves directly upon the chromaffin cells. Adrenaline was the first hormone to be discovered, in 1894 — an event which encouraged the search for similar chemical mediators in the body, and led to the creation of the specialty of endocrinology.

Unlike cortisol, which is produced exclusively in the adrenal cortex, adrenaline is produced in other parts of the body, including the brain, as well as in the adrenal medulla.

Like cortisol, adrenaline has widespread actions at many sites in the body, including the heart, lungs, and blood vessels, facilitating an increase in the supply of nutrients and oxygen. It also redeploys necessary fuels very rapidly, in readiness for immediate action if required: acting for example in the liver to enhance the release of glucose into the blood.

However, because adrenaline is produced in other areas of the body, removing the medulla does not seem to be a critical threat to life, though there does seem to be benefit in having adrenaline produced from the medulla at times of acute stress. Noradrenaline (norepinephrine), better known and most important as a neurotransmitter at sympathetic nerve endings, is also secreted by the medulla, along with adrenaline, but in much smaller amounts.

None of the adrenal hormones are released at a constant rate, but in amounts which change in response to various stimuli throughout the day.

In addition, in the case of cortisol and to a certain extent aldosterone, there is a gradual change of background levels in the blood over each 24-hour period.

This pattern of release is called a circadian rhythm, and is linked to the sleep-wake cycle of the individual — the ‘body clock’.

In the normal individual the greatest amounts of cortisol are released at about 8 o'clock in the morning; the level in the blood gradually falls during the day so that the lowest levels are found at about midnight.

ACTH also shows a circadian rhythm reaching maximum levels in the blood just before those of cortisol. The circadian rhythm of aldosterone is of much smaller amplitude than that of cortisol. Changing the times a person is asleep or awake will change the pattern of secretion; if shift workers sleep during the day and are awake at night then the circadian rhythm will be displaced by about 12 hours, with the highest blood levels of cortisol occurring in the early evening and the lowest levels about mid-day.

Similar changes occur when travelling across time zones. The shift in the circadian rhythm occurs gradually over a period of several days





Wikipedia: adrenal gland
Adrenal gland

Endocrine system

Adrenal gland
Latin glandula suprarenalis
Gray's subject #277 1278
System Endocrine


Anatomy and function
Anatomically, the adrenal glands are located in the thoracic abdomen situated atop the kidneys, specifically on their anterosuperior aspect. In humans, the adrenal glands are found at the level of the 12th thoracic vertebra and receive their blood supply from the adrenal arteries.

The adrenal gland is separated into two distinct structures, both of which receive regulatory input from the nervous system:

Adrenal medulla
As its name suggests, the adrenal medulla is the central core of the adrenal gland, surrounded by the adrenal cortex. The chromaffin cells of the medulla are the body's main source of the catecholamine hormones adrenaline (epinephrine) and noradrenaline (norepinephrine).

These water-soluble hormones, derived from the amino acid tyrosine, are part of the fight-or-flight response initiated by the sympathetic nervous system. The adrenal medulla can be considered specialized ganglia of the sympathetic nervous system, lacking distinct synapses, instead releasing secretions directly into the blood.

Adrenal cortex
By contrast, the adrenal cortex is devoted to the synthesis of corticosteroid hormones from cholesterol. Some cells belong to the hypothalamic-pituitary-adrenal axis and are the source of cortisol synthesis. Other cortical cells produce androgens such as testosterone, while some regulate water and electrolyte concentrations by secreting aldosterone. In contrast to the direct innervation of the medulla, the cortex is regulated by neuroendocrine hormones secreted by the pituitary gland and hypothalamus, as well as by the renin-angiotensin system.

Arteries and veins
Although variations of the blood supply to the adrenal glands (and indeed the kidneys themselves) are common, there are usually three arteries that supply each adrenal gland:

The superior suprarenal artery is provided by the inferior phrenic
The middle suprarenal artery is provided by the abdominal aorta
The inferior suprarenal artery is provided by the renal artery
Venous drainage of the adrenal glands is achieved via the suprarenal veins:

The right suprarenal vein drains into the inferior vena cava
The left suprarenal vein drains into the left renal vein or the left inferior phrenic vein.
The suprarenal veins receive blood may form anastomoses with the inferior phrenic veins.

The adrenal glands and the thyroid gland are the organs that have the greatest blood supply per gram of tissue.
Up to 60 arterioles may enter each adrenal gland.[1]


See also
Fight-or-flight response
Stress
Geoffrey Bourne

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

___________
function of the adrenal medulla -

The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex.


Function
Composed mainly of hormone-producing chromaffin cells, the adrenal medulla is the principal site of the conversion of the amino acid tyrosine into the catecholamines adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine.

In response to stressors such as exercise or imminent danger, medullary cells release catecholamines into the blood in a 85:15 ratio of adrenaline to noradrenaline. [1]

Notable effects of adrenaline and noradrenaline include increased heart rate and blood pressure, blood vessel constriction, bronchiole dilation, and increased metabolism, all of which are characteristic of the fight-or-flight response. Release of catecholamines is stimualted by nerve impulses, and receptors for catecholamines are widely distributed throughout the body.

http://www.answers.com/adrenal%20medulla


also
http://tripatlas.com/Chromaffin_cells
http://tripatlas.com/Adrenal

PD and chromaffin cells
http://www3.interscience.wiley.com/j...TRY=1&SRETRY=0