Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin

Publication date: Available online 3 October 2018Source: Pharmacology & TherapeuticsAuthor(s): Alaeddine Djillani, Mariel Pietri, Jean Mazella, Catherine Heurteaux, Marc BorsottoAbstractDepression is a devastating mood disorder and a leading cause of disability worldwide. Depression affects approximately one in five individuals in the world and represents heavy economic and social burdens. The neurobiological mechanisms of depression are not fully understood, but evidence highlights the role of monoamine neurotransmitter balance. Several antidepressants (ADs) are marketed to treat depression and related mood disorders. However, despite their efficacy, they remain nonspecific and unsafe because they trigger serious adverse effects. Therefore, developing new molecules for new targets in depression has become a real necessity. Eight years ago, spadin was described as a natural peptide with AD properties. This 17-amino acid peptide blocks TREK-1 channels, an original target in depression. Compared to the classical AD drugs such as fluoxetine, which requires 3–4 weeks for the AD effect to manifest, spadin acts rapidly within only 4 days of treatment. The AD properties are associated with increased neurogenesis and synaptogenesis in the brain. Despite the advantages of this fast-acting AD, the in vivo stability is weak and does not last for>7 h. The present review summarizes different strategies such as retro-inverso strategy, cyclization, and shortening the spadin sequence...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research