text: TrkB agonists have received extensive interest from the scientific community resulting in the synthesis and biological evaluation of a large number of mimetics. Deoxygedunin, with a selective TrkB activity, is able to promote axon regeneration in topical treatments. Furthermore, it shows efficacy in two Parkinsons disease (PD) animal models, leading to the protection of locomotor function and the reduction of neuronal death in dopaminergic neurons. A number of studies corroborated that the flavonoid 7,8-Dihydroxyflavone (7,8-DHF) shows neuroprotection in PD and Huntingtons disease (HD) models together with antioxidant activity and enhancement of motor neuronal survival, motor function and spine density in amyotrophic lateral sclerosis (ALS) model. The benzothiazole riluzole exerts neuroprotective effects by increasing BDNF and GDNF levels with improvement of motor neuron survival. It has been approved for the treatment of ALS and delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Furthermore, several combinations of riluzole with other drugs are in clinical trials (NCT02588677, NCT03127267).
  Brimonidine exerts neuroprotective effects in retinal ganglion cells (RGCs) through up-regulation of the expression of BDNF in these cells. It is used in the treatment of glaucoma as eye drops to reduce intraocular pressure (IOP) under the brand name Lumify®. Different drugs, used against PD also behave as neurotrophin mimetics such as rotigotine, selegiline, rasagiline, memantine and levodopa interacting with TrkB and increasing BDNF expression. Furthermore, of particular note, the groups of F. Longo and S. Massa discovered small molecule neurotrophic mimetics exhibiting specificity for TrkB at nanomolar concentrations. In particular, LM22A-4, prevents neuronal death in in vitro models of AD, HD and PD.
  Among the peptidomimetic TrkB agonists, the dimeric dipeptide GSB-106 showed neurotrophic and neuroprotective effects by specific activation of TrkB and its signaling pathways. Furthermore, the tricyclic dimeric peptide TDP6 acts as a TrkB agonist mimicking BDNF and induces autophosphorylation of TrkB in primary oligodendrocyte cultures, leading to oligodendrocyte myelination. Regarding DHEA derivatives, the C17-spiroepoxy analogue, BNN-20, binds with high affinity to TrkB, showing antiapoptotic activity in vitro. Its neuroprotective activity was analyzed in the Weaver mouse genetic model of PD in which long term administration of BNN-20 protects the dopaminergic neurons by mimicking BDNF and induces antiapoptotic, antioxidant and anti-inflammatory effects.