Tumor Necrosis Factor Alpha and Fas Receptor Contribute to Cognitive Deficits Independent of Cell Death after Concussive Traumatic Brain Injury in Mice

Abstract

Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (P<0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P=0.009) and probe deficits (P=0.001) in the Morris water maze versus sham. Surprisingly, injured TNFα/Fas knockout (KO) mice performed worse in hidden platform trials (P=0.036) but better in probe trials than did WT mice (P=0.0001). Administration of recombinant TNFα to injured TNFα/Fas KO mice reduced probe trial performance to that of WT. Thus, TNFα/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI.

Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

“…But, it is not known whether the protection is associated with selective upregulation of TNF-a expression by LLLT at an early stage of the disorder, while inhibiting the expression of other antiinflammatory mediators. TNF-a-deficient mice exhibited an early functional improvement but failed to fully recover over time after TBI, 38 raising an intriguing possibility that an outcome of TNF-a on brain injury depends on the presence of other proinflammatory cytokines. For instance, TNF-a was found to synergistically enhance the neurotoxic effects of IL-1b as both shared many of the same physiologic effects.…”

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

“…The finding that Akt/mTOR pathways are activated after CHI in the hippocampus (Figures 1 and 2), a site for significant morphological activation of astrocytes and microglia, 21 and that administration of rapamycin worsens hidden platform and probe trial performance ( Figure 5), suggests that glia-specific protein synthesis (mediated by Akt/mTOR) may also contribute to cognitive outcome after CHI. In normal (uninjured) brain, microglia and astrocytes contribute in distinct ways to synaptic function, learning, and memory.…”

“…The current findings have potential treatment implications for TBI patients and design of clinical trials: Akt and mTOR inhibitors might improve outcome in patients with cerebral contusion, 13 but their use could be detrimental in patients with concussive or 'diffuse' TBI. 21 In patients with both concussive and contusion injury subtypes, the net result of Akt/mTOR inhibition on postinjury cognitive function may be unpredictable. The current study underscores the importance of testing small-molecule inhibitors in diverse preclinical models with different pathoanatomic subtypes to help inform clinical trials for patients with TBI.…”

“…The model does not produce hypoxia or hypotension, edema, blood-brain barrier damage, or acute and chronic cell death/tissue loss, and mice regain consciousness typically within 2-7 minutes after injury. 21 …”

“…The purpose of the current study was to determine whether Akt and mTOR activation occurs after concussive TBI in a model devoid of acute cell death, 21 and whether these pathways might contribute to postinjury cognitive outcome. In addition, we sought to examine whether Nec-1 may have beneficial effects on outcomes related to Akt activation.…”