Delayed Administration of a Small Molecule Tropomyosin-Related Kinase B Ligand Promotes Recovery After Hypoxic–Ischemic Stroke

Abstract

Background and Purpose Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor (BDNF) stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B (TrkB) and p75 neurotrophin (p75NTR) receptors. However, BDNF is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets TrkB would promote neurogenesis and functional recovery after stroke. Methods Four-month-old mice were trained on motor tasks prior to stroke. After stroke, functional test results were used to randomize mice into two equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for ten weeks. Results LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. Conclusion A small molecule agonist of TrkB improves functional recovery from stroke and increases neurogenesis when administered beginning three days after stroke. These findings provide proof-of-concept that targeting of TrkB alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as “pro-recovery” therapeutic agents for stroke.

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 absence of p75 NTR binding makes LM22A-4 distinct from a "BDNF mimetic" that would evoke a full range of BDNF-related activities. LM22A-4 prevents quinolinic acid-induced striatal neuron death, crosses the blood-brain barrier to activate TrkB and its associated signaling, including AKT and ERK (Massa et al, 2010), and ameliorates motor deficits and pathology in rodent models of traumatic brain injury, stroke, and Rett syndrome (Massa et al, 2010;Han et al, 2012;Schmid et al, 2012). This study was undertaken to determine whether specifically activating TrkB with LM22A-4 can alleviate HD-related striatal pathology, including huntingtin aggregates and dendritic spine loss, and motor disturbances, using R6/2 and BACHD HD mouse models.…”

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…[24][25][26][27][28][29][30][31] Additionally, there are a number of compounds that have a longer therapeutic 1 window presumably because they promote neuronal migration, neurogenesis, and oligodendrogenesis. 32,33 We propose stem cell therapy as an additional strategy to regenerate the damaged brain areas with a potentially longer therapeutic time window. Recent work by our group and others support the concept that stem cell transplantation may have therapeutic potential with a relatively long time window by repairing the already damaged brain.…”