Activating toll-like receptor 4 after traumatic brain injury inhibits neuroinflammation and the accelerated development of seizures in rats

Toll-like receptor 4 (TLR4) signaling plays a detrimental role in traumatic brain injury (TBI) pathology. Phar-macologic or genetic inactivating TLR4 diminish TBI inflammation and neurological complications. Nonetheless, TLR4 priming alleviates TBI inflammation and seizure susceptibility. We investigated impact of postconditioning with TLR4 agonist monophosphoryl lipid A (MPL) on TBI neuroinflammation and epileptogenesis in rats. TBI was induced in temporo-parietal cortex of rats by Controlled Cortical Impact device. Then rats received a single dose (0.1 mu g/rat) of MPL by intracerebroventricular injection. After 24 h, CCI-injured rats received intraperitoneal injection of pentylenetetrazole 35 mg/kg once every other day until acquisition of generalized seizures. The injury size, number of survived neurons, and brain protein level of TNF-alpha, TGF-8, IL-10, and arginase1 (Arg1) were determined. Astrocytes and macrophage/microglia activation/polarization was assessed by double im-munostaining with anti GFAP/Arg1 or anti Iba1/Arg1 antibodies. The CCI-injured rats developed generalized seizures after 5.9 & PLUSMN; 1.3 pentylenetetrazole injections (p < 0.001, compared to 12.3 & PLUSMN; 1.4 injections for sham -operated rats). MPL treatment returned the accelerated rate of epileptogenesis in TBI state to the sham -operated level. MPL did not change damage volume but attenuated number of dead neurons (p < 0.01). MPL decreased TNF-alpha overexpression (6 h post-TBI p < 0.0001), upregulated expression of TGF-8 (48 h post-TBI, p < 0.0001), and IL-10 (48 h post-TBI, p < 0.0001) but did not change Arg1 expression. GFAP/Arg1 and Iba1/Arg1 positive cells were detected in TBI area with no significant change following MPL administration. MPL admin-istration after TBI reduces vulnerability to seizure acquisition through down regulating neural death and inflammation, and up-regulating anti-inflammatory cytokines. This capacity along with the clinical safety, makes MPL a potential candidate for development of drugs against neurological deficits of TBI.

Automated summary

Toll-like receptor 4 (TLR4) signaling has a detrimental role in traumatic brain injury (TBI) pathology. However, TLR4 priming can alleviate TBI inflammation and seizure susceptibility. In this study, we found that postconditioning with TLR4 agonist monophosphoryl lipid A (MPL) reduces TBI neuroinflammation and epileptogenesis by decreasing neural death and inflammation, while upregulating anti-inflammatory cytokines.