Disrupting Protein-Protein Interaction: Therapeutic Tools Against Brain Damage

Abstract

Brain damage caused by stroke, epilepsy, head and spinal trauma, and degenerative neurological conditions represents a significant source of morbidity and mortality in Westernized society. Neuronal death occurs as a result of a complex combination of excitotoxicity, necrosis, apoptosis, edema, and inflammatory reactions. Neuroprotection via glutamate receptor blockade, antioxidant, or anti-inflammatory therapy have not proven effective in clinical treatment of brain damage because of narrow therapeutic windows, poor pharmacokinetics or blockade of signaling essential for normal excitatory neurotransmission and neuronal survival. Recent work in neuronal biochemistry, genomics, and proteomics has increased understanding of the molecular organization of the excitatory synapse and the neuronal postsynaptic density. This understanding in kind has led to the dissection of the intracellular signaling cascades responsible for excitotoxicity. In addition, we have increased our understanding of the intracellular and extracellular signaling, networks responsible for apoptosis and inflammation. It has thus become possible to uncouple toxic second messenger pathways from their membrane receptors by targeting the interactions between the receptor and downstream proteins. In addition the use of cell-permeable protein transduction domains now allows for the design of fusion peptides and small proteins for in vivo therapies while overcoming limitations of poor cell membrane permeability and in the instance of neurological disorders, poor delivery across the blood-brain barrier. This technology, together with an intricate knowledge of the enzymes, protein networks, and signaling mechanisms related to evolution of brain pathology, will aid in the design of future effective therapeutics.