TrkB Receptor Agonist 7,8-Dihydroxyflavone and Its Therapeutic Potential for Traumatic Brain Injury

Introduction

Approximately 350,000 individuals in the United States are affected annually by severe and moderate traumatic brain injuries (TBIs) that may result in long-term disability. This rate of injury has produced over 3 million disabled citizens in the United States alone. Despite generally improving rates of survival after TBI, approximately 80,000 individuals in the United States annually sustain TBIs that result in significant long-term disability. These impairments involve both sensory motor and cognitive functions and can result in a total vegetative state. Most of these 3 million TBI survivors depend upon others for daily care. Many clinical and animal model studies have now shown that severe and even moderate TBI is characterized by both neuronal and white matter loss with resultant brain atrophy and functional neurological impairment. Injury may be in the form of focal damage, as typically occurs after acute subdural hematoma, or it may be diffuse with widespread delayed neuronal loss as typically occurs after diffuse axonal injury.

TBI can be described as a loss of brain function due to an external mechanical force. The cells and tissue that are directly injured upon impact, including neurons, glia, blood vessels, and axons, are considered primary damage ( ). Following the primary injury, the subsequent secondary injury induces further tissue loss in the surrounding tissues of the initial impact site. Many biochemical processes, such as excess excitotoxin release, increased intracellular calcium concentration, lipid peroxidation, inflammatory mediators, and the production of free oxygen radicals, contribute to the secondary damage ( ). Secondary injury can occur over days to weeks after TBI ( ) and result in diffuse neurodegeneration that affects motor and cognitive function ( ). To date, there is no effective treatment for TBI. Current therapies are primarily focused on reducing the extent of secondary insult rather than repairing the damage from the primary injury.

To reduce secondary injury, strategies which have neuroprotective effect salvaging the injured brain tissue in the early stage postinjury and promote regeneration at the recovery stage are desirable. The brain-derived neurotrophic factor (BDNF) and its high affinity receptor tropomyosin receptor kinase B (TrkB) play a critical role in neuronal differentiation and survival, synapse plasticity, and memory. Targeting BDNF/TrkB signaling pathway has a remarkable therapeutic potential for many neurological disorders including TBI. This chapter will review recent understanding and progress in experimental TBI therapeutic development targeting this signaling pathway with focus on the potential of TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) for treating TBI ( Fig. 14.1 ).

Neurotrophins and Tropomyosin Receptor Kinase B Receptor

Neurotrophins are a group of polypeptides with great influence on neuronal differentiation, survival, axon growth, and synaptogenesis in the central nervous system (CNS) and peripheral nervous system (PNS) ( ). The neurotrophin family members include nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). In the CNS, both neuronal and nonneuronal cells synthesize neurotrophins in a precursor form, or proneurotrophin form. The immature proteins are then either secreted or cleaved by plasmin or extracellular proteases into the mature form ( ).

The diverse effects that occur at the presence of neurotrophins are a result of the ligand-receptor binding and the specific signal cascades that follow. This includes two transmembrane-receptor signaling systems that consist of the p75 neurotrophin receptor (p75 ^NTR ) and the tyrosine kinase receptors: TrkA, TrkB, and TrkC. The p75 ^NTR belongs to the tumor necrosis factor (TNF) receptor super family while the tyrosine kinase receptors belong to the tropomyosin receptor kinase (Trk) family ( ). The Trk family of receptors is instrumental in carrying out the cellular effects of neurotrophins. Among Trk family receptors, TrkB acts as a receptor for BDNF and NT-4 ligands. NT-3 binds to TrkC and can also bind TrkB with a reduced affinity. NGF has a higher affinity for TrkA ( ). It is through high-affinity binding for TrkB that neurotrophin is able to provide neuronal survival, neuronal plasticity, and neurogenesis ( ), whereas binding with the p75 ^NTR receptor is more associated with apoptosis. Both TrkB and p75 ^NTR receptors can be found in the same cell, coordinating and modulating neuronal responses. Furthermore, the signals generated by each receptor can augment each other or go against each other, fluctuating between an enhancing and suppressing relationship ( ).