Emerging molecular targets for brain repair after stroke

Abstract

The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinics. The approaches that combine the modulation of the inhibitory environment together with the promotion of intrinsic axonal outgrowth needs further work before combined therapeutic strategies will be transferable to clinic trials. It is likely that only when some answers have been found to these issues will our therapeutic efforts meet our expectations. Stroke is a clinically heterogeneous disease and combinatorial treatments require much greater work in pharmacological and toxicological testing. Advances in genetics and results of the Whole Human Genome Project (HGP) provided new unknown information in relation to stroke. Genetic factors are not the only determinants of responses to some diseases. It was recognized early on that "epigenetic" factors were major players in the aetiology and progression of many diseases like stroke. The major players are microRNAs that represent the best-characterized subclass of noncoding RNAs. Epigenetic mechanisms convert environmental conditions and physiological stresses into long-term changes in gene expression and translation. Epigenetics in stroke are in their infancy but offer great promise for better understanding of stroke pathology and the potential viability of new strategies for its treatment.

Figure 1

There are three main epigenetic mechanisms. (1) The first includes the mechanisms mediating DNA methylation, typically at cytosine residues in gene promoter regions. These reactions attenuate gene expression and are catalyzed by multiple different isoforms of DNA methyltransferases. An important requirement for these reactions is a methyl donor, typically folic acid supplied through the diet. (2) The second epigenetic category of mechanisms includes the enzymes that acetylate and deacetylate lysine residues on histone proteins. These enzymes regulate chromatin structure and include histone acetyltransferases and histone deacetylases. In general, histone acetylation promotes dissociation from DNA and facilitates gene expression, whereas deacetylation promotes reassociation and reduced gene expression. (3) The third epigenetic category includes the pathways that transcribe, process, and transport microRNA, endogenous short interfering RNAs (siRNAs), and exogenous siRNAs. Endogenous microRNAs are transcribed from nuclear genes into primary microRNA transcripts, which are cleaved into precursor microRNA transcripts. The nuclear protein, Exportin 5, transports precursor microRNAs onto the cytoplasm, where it is cleaved by Dicer to an imperfect miR-X : miR-X* duplex. One strand of the duplex is degraded and the remaining, mature microRNA binds Dicer and Argonaute (Ago) proteins to form RNA-induced silencing complexes (RISCs). MicroRNAs target sequences within cellular mRNAs. Parallel processes in the cytoplasm produce siRNAs derived from endogenous transposons, or from exogenous siRNAs and target cellular or viral mRNAs.