Abstract
Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.
Highlights
Traumatic brain injury (TBI), which encompasses a wide spectrum of injuries from mild to severe, has been regarded as a “silent epidemic of modern society”[1]
The ability of tropomyosin-related kinase B (TrkB) signaling to be neuroprotective in neuroinflammatory settings[24, 25], prompted us to test if CN2097, a peptidomimetic compound enhancing downstream TrkB signaling[12], can attenuate the brain inflammatory response to injury
Focusing on monocytes, whose influx to the injured brain could be readily assessed by the levels of expression of CD68 at 1 d post-TBI26, we found that CN2097 reduces the post-traumatic influx of these inflammatory cells (Fig. 1B, upper panel)
Summary
Traumatic brain injury (TBI), which encompasses a wide spectrum of injuries from mild to severe, has been regarded as a “silent epidemic of modern society”[1]. For patients who survive the initial trauma, morbidity and mortality are largely determined by the severity of secondary injury resulting from pathophysiological processes that lead to neuronal death[2]. The initial injury in TBI triggers glutamate release leading to hyperactivation of N-methyl-D-aspartate (NMDA)-type receptors (NMDARs), calcium (Ca2+) overload, and secondary neuronal death due to excitotoxicity[3]. Increased levels of glutamate activate microglia[2], to release proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)[14, 15], to suppress BDNF-dependent signaling and LTP16. CN2097 binding to PSD-95 promotes PSD-95 recruitment to TrkB to enhance BDNF-mediated PLCγ-CaMKII and PI3K-Akt signaling, but not ERK, to facilitate LTP in the hippocampus[12]. In contrast to previously reported PSD-95 PDZ-binding peptides that disrupt the function of PSD-9521, CN2097 facilitates LTP12 and pro-survival signaling[13]. The single dose of CN2097 tested in this study did not improve all therapeutic endpoints routinely evaluated in experimental TBI, taken together, our results strongly suggest that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma
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