Depression inflicts a large number of human beings under their lifetime. In addition to suffering and a considerable risk for suicide, the disease is associated with major cost for Society.

Different types of treatment of depression are available. Often it is pharmacological, for example with SSRIs, e.g. Prozac. Even if this treatment is successful in around 60% of patients, there are problems with resistance, side effects and late onset of the therapeutic effect.

Against this background, researchers at Karolinska Institutet are searching for new targets for development of improved antidepressants. Among targets are receptors for neuropeptides, a large group of neurotransmitters. Galanin is a 29/30 amino acid long neuropeptide that acts via three receptors, GalR1-3.

Studies show an anti-depressive effect

Galanin, which was purified from porcine intestine, was discovered more than 30 years ago by Viktor Mutt and his PhD student Kazuhiko Tatemoto at KI. This peptide has since then been studied with focus on depression by several groups at KI and Stockholm university. Extensive animal experiments suggest that the GalR1 antagonist could have antidepressive effect.

Swapnali Barde and collaborators have now investigated to what extent the results from animal experiments are relevant for humans. Five regions were studied in post-mortem brains from depressed women and men that had committed suicide and from controls.

"We use three methods for analysis of galanin and the three receptors: qPCR to measure levels of transcript (mRNA), prosequencing to measure DNA methylation (epigenetic changes) and radioimmunoassay, the latter however only to measure concentrations of galanin", says one of the authors, Tomas Hökfelt.

Results show a difference between sick and healthy brains especially in the frontal lob and in two nuclei in the lower brain stem, various anterior cingulum was not affected at all. Furthermore, it was especially the transmitter cells, that is galanin and GalR3 that show changes. Both were upregulated in the brain stem nuclei and downregulated in the frontal lobe.

"At the same time the methylation was changed in the opposite direction, which is in agreement with a theory that methylation suppresses synthesis. The changes were seen both in women and men", Tomas Hökfelt continues.

Fewer side effects expected

GalR3 coexists both with noradrenalin and 5-hydroxytryptamin in separate nerve populations in the nuclei mentioned above in the lower brain stem. GalR3 is an inhibitor receptor that slows down activity in these nerve cells and in this way reduces release of NA and 5-HT in the forebrain. Since the transcript for both galanin and GalR3 are upregulated, these likely results in reduction in activity of these two monoamines in the forebrain in depression. A GalR3 antagonist could as medicine thus possible have an antidepressant effect by inhibiting ‘the break’.

"The end result is similar to what SSRIs and similar medicine cause, namely to increase the brains content of 5-HT and NA – but via a completely different mechanism. The expectation is that a GalR3 antagonist also would act faster, that is without delay, as well as have fewer side effects", concludes Tomas Hökfelt.

Publication

"Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide"

Swapnali Bardea, Joelle Rüegg, Josée Prud’homme, Tomas J. Ekström, Miklos Palkovits, Gustavo Turecki, Gyorgy Bagdy, Robert Ihnatko, Elvar Theodorsson, Gabriella Juhasz, Rochellys Diaz-Heijtz, Naguib Mechawar, Tomas G. M. Hökfelt

PNAS. Published online 9 December 2016.doi: 10.1073/pnas.1617824113