Clarifying the effects of LM22A4
Description
Spinal cord injury (SCI) can cause dramatic loss of motor, sensory, and autonomic function, with no gold-standard intervention currently available. Activation of tropomyosin receptor kinase B (TrkB) by brain-derived neurotrophic factor (BDNF) is known to promote neuronal survival and neurite extension and has consequently been a focus of SCI repair strategies. However, BDNF's instability in solution and poor pharmacokinetic properties, have made its clinical translation problematic. LM22A-4, a small molecule partial agonist of TrkB mimicking the type II loop of BDNF, has been proposed as a more stable alternative, though its potency, efficacy, and mechanism of action have been increasingly questioned in recent literature. Herein, we assessed LM22A-4 against BDNF across several in-vitro models relevant to SCI pathology, including dorsal root ganglion (DRG) neurite outgrowth, glutamate-induced excitotoxicity in differentiated SH-SY5Y cells, and motor neuron differentiation from induced pluripotent stem cells (iPSCs). LM22A-4 (10 µM) significantly increased DRG mean neurite length to a comparable degree to BDNF, whilst both lower and higher concentrations (1, 33, and 100 µM) showed little to no effect, suggesting a narrow window of efficacy. Following glutamate insult, LM22A-4 conferred modest, concentration-dependent neuroprotection in the acute (30-minute) model, but did not replicate BDNF's protective effect in a prolonged (96-hour) model, although it did partially preserve neurite length and reduced neurite beading. Neither LM22A-4 nor BDNF significantly increased ChAT-positive motor neuron yield from iPSCs, indicating a limited capacity to direct neuronal fate. Taken together, LM22A-4 was found to recapitulate some, but not all, of BDNF's functional effects across these models. These findings add to a growing body of literature that brings LM22A-4's mechanism of action into question and support the need for further mechanistic and in-vivo investigation.