A treatment for depression that up regulates BDNF will also be a treatment for HD. Many thanks to Kjell Fuxe, professor of neuroscience at Karolinska. --Jerry

Posted to HDLighthouse:04-Sep-2002 HDL Update: The Common Path To Depression

Important BDNF Finding From Karolinska Institute in Stockholm, Sweden "The normal physiological role of BDNF is to encourage the outgrowth of tiny processes called dendrites from nerve endings, and to help stabilize connections between neurons", Prof. Kjell Fuxe.

Kjell Fuxe, professor of neuroscience at the Karolinska Institute in Stockholm, Sweden, today presented his hypothesis together with unpublished data that explains how both stress and a loss of the "feel-good factor" 5HT (serotonin) can lead to depression via the same mechanism. What they have in common is that they both act on brain derived neurotrophic factor (BDNF). The normal physiological role of BDNF is to encourage the outgrowth of tiny processes called dendrites from nerve endings, and to help stabilize connections between neurons.

The new hypothesis suggests that stress hormones and 5HT work in opposition: stress hormones decreasing levels of BDNF, and 5HT increasing them. If the normal balance is tipped too far to one side, such as with chronic stress, the resulting loss of BDNF leads to an altered output from areas such as the hippocampus to the pre-frontal cortex. This highlights BDNF as one of several new targets for drug development, claims Fuxe.

"This is a nice future for neuroendocrinology - to bring in the steroids with the transmitters and the neurotrophic factors. With all of them coming together this will help us to understand depression and get the novel treatments to come about," Fuxe told BioMedNet News.

Researchers already knew that glucocorticoid and mineralocorticoid hormones, released from the adrenal glands during stress, contribute to depression by acting on the hippocampus. When these hormones bind to specific receptors in this region they cause a drop on the levels of both BDNF mRNA and protein in neurons.

On the other side of the equation, the loss of 5HT is also well known to contribute to depression - leading to the development of now widely used serotonin-reuptake inhibitors (SSRIs) such as Prozac. These inhibit a set of receptors that normally mop up what little 5HT remains in the extracellular space, thus boosting its signaling capacity closer to normal levels.

But the two processes are not normally viewed as being part of the same overall picture, says Fuxe.

"I think this has never been put forward before - this balance between 5HT transmission and glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in their control of BDNF," he said.

Fuxe unveiled data showing that GR triggering leads to the binding of intracellular signaling proteins to exon IV of the BDNF promotor sequence, thus directly inhibiting gene expression.

His team has also found that the expression of the gene c-fos could counteract this inhibition by GR activity, revealing a new internal level of regulation of BDNF expression.

Whether a particular neural network will succumb to the effects of stress hormones, however, will also depend on the levels of 5HT.

"A very bad depression is when a lot of MR/GR is activated, inhibiting BDNF, as well as very low 5HT," said Fuxe. The greater the imbalance, according to his hypothesis, the greater the depression.

Other factors released during stress, such as the neuropeptide galanin, can also reduce the signaling ability of 5HT by binding to its receptors, thus reinforcing the inhibitory effects on BDNF expression. It may even be that glucocorticoids also reduce 5HT expression directly, according to other data not presented today.

"The novel thing here is to bring all these hypotheses together into one single story. Some major players are still outside but we have the 5HT, we have the galanin, we have the MR/GR, and it's all focusing down on BDNF," said Fuxe. "There could be other neurotrophic factors involved that we are not fully aware of at the moment," he added.

BDNF regulation therefore provides a new therapeutic approach, but no such candidate drugs are in development. "This will be an important issue for the future," said Fuxe. !

Source: International Congress of Neuroendocrinology Report, The Common Path To Depression -- 02Sep-2002

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