Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

Abstract

Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin NT-4/5, a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion injury in rats, compared to 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.

Caffeic Acid Phenethyl Ester Protects Blood–Brain Barrier Integrity and Reduces Contusion Volume in Rodent Models of Traumatic Brain Injury

“…The rats were tested for their cognitive performance using the standard hidden platform version of the Morris water maze (MWM; Dash et al, 1995Dash et al, ,2002Hamm et al, 1992;Royo et al, 2007). All animals had recovered from the TBIassociated motor dysfunction prior to performing the cognitive testing.…”

Identification of Potentially Neuroprotective Genes Upregulated by Neurotrophin Treatment of CA3 Neurons in the Injured Brain

“…Indeed, mice lacking endogenous NT-4/ 5 (NT-4/5 À/À knockout mice), when matured to adulthood, showed increased CA pyramidal cell death after brain injury compared to littermate controls, indicating that NT-4/5 is an endogenous neuroprotectant for these CA neurons. Finally, brain infusion of recombinant NT-4/5 rescued approximately half of the vulnerable population of CA pyramidal neurons after experimental brain injury in rats (Royo et al, 2006(Royo et al, , 2007. Together, these results strongly suggest a neuroprotective role for NT-4/5 following TBI.…”

“…Under pentobarbital anesthesia, adult male Sprague-Dawley rats (350-400 g; Harlan Laboratories, Indianapolis, IN) were subjected to a single lateral fluid percussion (LFP) brain injury (2.65-2.75 atm), or remained uninjured (SHAM) as controls. Lateral fluid percussion injury and brain cannulation were performed exactly as previously described (Royo et al, 2007). …”

“…Several lines of evidence indicate that the mammalian neurotrophin-4/5 (NT-4/5) is neuroprotective for vulnerable CA3 pyramidal neurons in the hippocampus after experimental TBI (Royo et al, 2006(Royo et al, , 2007. Endogenous NT-4/5 protein levels are transiently elevated in the hippocampus after brain injury.…”

Peptide-mediated targeting of liposomes to TrkB receptor-expressing cells

“…37 However, administration of TrkB ligands to neurons may not result in neuroprotection, or neuronal survival, and apoptotic signaling by TrkB ligands such as brain-derived neurotrophic factor, has also been demonstrated via activation of an alternative receptor, p75NTR. 38 In this context, TrkB-targeting liposomes without p75NTR-targeting should be capable of intracellular delivery of survival genes, without adverse induction of apoptosis, thus representing a promising option for neuroprotection.…”