Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

Abstract

Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

“…37 Importantly, previous studies have shown that administration of the TrkB ligand, LM22A-4, binds and actives downstream signaling pathways including AKT and ERK, 13 and can ameliorate motor impairments in the model of both traumatic brain injury and stroke. 13,14 Consistent with this, we also report that multiple signaling pathways are activated in response to CX1837 and BDNF treatments, and include an increase in p-AKT, p-ERK, and p-MEK. As CREB deletion only partially blocked the recovery afforded by combined treatment of CX1837 and local BDNF delivery, other signaling pathways, in addition to the proposed AKT/GSK-3/CREB pathways, are likely to be playing a role in recovery.…”

“…6 We have also shown that CX1837-mediated functional recovery occurred in a BDNF/TrkB-dependent manner, a finding that has been confirmed by Massa et al who further identified the role of downstream protein kinase B (AKT) and extracellular signalregulated kinase (ERK) signaling pathways. 13,14 One significant, issue that has yet to be addressed is whether CX1837 retains its effectiveness in aged populations, as it is now widely recognized that BDNF activity is significantly impaired with age. 15,16 As aging alters the responsiveness of the cortex, and how tropic factors may act, it is likely that cotreatments will afford greater recovery after stroke in aged populations.…”

A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease

“…The rationale for targeting TrkB in HD is based not only on BDNF deficiencies but also on multiple linkages between the receptor's signaling and underlying HD degenerative mechanisms. Our laboratories identified small molecule TrkB ligands with structures similar to loop II of BDNF (Massa et al, 2010), a region that confers TrkB activation and specificity (Longo and Massa, 2013). One such ligand, [N,NЈ,NЉ-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide)] (LM22A-4), binds to TrkB but not other Trks or p75 NTR , and had a negative receptor binding screen (Cerep).…”

Rett Syndrome: Reaching for Clinical Trials

“…Peripheral treatment with ampakines significantly improved respiratory function in male Mecp2 knockout mice [86], which phenocopies the recurrent apneas suffered by individuals with RTT. BDNF loop domain mimetics are small molecules designed in silico to interact with the BDNF binding pocket in the TrkB receptor [87]. One of them, LM22A-4, restored respiratory regularity in female Mecp2 heterozygous mice [88,89], increased dendritic spine density in CA1 pyramidal neurons in organotypic slice cultures of male Mecp2 knockout mice (Miller, Longo, and LP-M, in preparation), and restored long-term potentiation at CA3->CA1 excitatory synapses in hippocampal slices from symptomatic female Mecp2 heterozygous mice (Li, Longo, and LP-M, in preparation).…”