In recent years it has been shown that the peptide hormone insulin can directly interact with nerve terminals in fenestrated capillaries in the circumventricular organs of the brain. This is thought to be an important step in the development of new therapeutic approaches for the treatment of psychiatric disorders such as bipolar disorder and depression. This article will discuss the discovery of a number of peptides that can directly interact with insulin receptors in these fenestrated capillaries and will describe how they might be used to treat psychiatric disorders.
The direct peptide reactivity assay (DPRA) is an in vitro method for the detection of skin sensitizers that has been approved by OECD as a non-animal alternative to the white rabbit test. It measures the reactivity of a chemical compound by testing it with a cysteine-containing model peptide. A series of concentrations and incubation times are tested to generate a data matrix of DP values, which is analysed to give a reactivity parameter logkmax. If logkmax exceeds a cut-off value of -2, the chemical is classified as a potential sensitiser in the OECD 1A potency class.
The kDPRA is an amendment of the DPRA and aims to improve the predictive performance by measuring the kinetics of the interaction between the chemical and the peptide. This is achieved by adding the reactivity marker monobromobimane to the reaction mixture in order to measure the proportion of free cysteine that is not depleted by the anhydride, after which a kinetic measurement of the depletion is made using fluorescent peptide reagents. It was found that the kDPRA is technically feasible for testing multi-constituent substances and mixtures of known composition, but it should be noted that the kDPRA data analysis protocol is not suitable for measuring reactivity to anhydrides that are unable to react with the peptide thioester to form a peptide-anhydride adduct that can then be hydrolysed. direct peptides