Abstract
Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling.
Highlights
Neurological disorders ranging from epilepsy to Alzheimer’s disease (AD), from stroke to Parkinson’s disease (PD), are currently estimated to affect as many as a hundreds of millions of people worldwide, and the number is expected to increase considerably in years to come
A novel study has discovered that one specific enantiomer of a ketamine metabolite can exert rapid and sustained antidepressant actions in mice, which are independent of NMDAR inhibition but require AMPAR activation, while lacks ketamine unwanted side effects [192]. Both gradually and rapid acting antidepressants reverse the significant decrease of brain-derived neurotrophic factor (BDNF) levels characteristic of major depressive disorder (MDD) patients [193] and promote tropomyosin-related kinase B (TrkB) signalling, synaptic plasticity and neuronal excitability
Brain TrkB transactivation is achieved by antidepressant drugs in adult mice via unknown mechanisms [16] that result in specific phosphorylation of Tyr816, PLCγ activation and CREB phosphorylation [151], processes that are independent of monoamine transporter inhibition or BDNF action [203]
Summary
Neurological disorders ranging from epilepsy to Alzheimer’s disease (AD), from stroke to Parkinson’s disease (PD), are currently estimated to affect as many as a hundreds of millions of people worldwide, and the number is expected to increase considerably in years to come. The secreted TrkB ectodomain, common to both isoforms contains the receptor domain important for ligand interaction and specificity and acts as a BDNF scavenger (Figure 2f) reducing even further the neurotrophic signalling [34]. These results reflect an endogenous capacity of the brain to promote neurotrophic signalling after cerebral damage which is subverted by a truncation of the downstream signalling pathways, mainly at the receptor level, that blocks a proper neuronal survival response.
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