The Toll-like receptor 1/2 ligand Pam3Cys inhibits memory impairment after traumatic brain injury in male and female rats.

Amnesia is common after traumatic brain injury (TBI). Toll-like receptor 1/2 agonist, tri-palmitoyl-S-glyceryl-cysteine (Pam3Cys), prevents TBI neuroinflammation. We investigated Pam3Cys potential to ameliorate TBI amnesia, and discerned the effect between male and female. Male and female adult rats were trained in the Morris water maze (n = 160) and shuttle box (n = 80). Then, animals received mild TBI by controlled cortical impact. Twenty min after TBI, Pam3Cys was injected by intra-cerebroventricular route. Spatial memory was assessed 7 and 28 days whereas avoidance memory was evaluated 2 and 6 days after TBI. Brain damage was evaluated by TTC and Nissl staining. Rats effectively learned, with no sex difference, spatial and avoidance tasks by progressive decrease in latency and distance to platform, and avoiding shock chamber during training. One week after acquisition, memory retrieval was disrupted in naïve female rats which traveled 22% more than males to reach platform position (P < 0.01). At four weeks, sham-operated female rats spent 26% less time than males in platform position (P < 0.01). TBI significantly disrupted both spatial and avoidance memories at all measured times. Spatial memory of females showed greater impairment than males at four weeks after TBI (40% less presence in platform position, P < 0.01). No sex difference existed in avoidance memory under control or TBI. Pam3Cys reduced TBI-induced latency increase in both sexes at one week (P < 0.05, P < 0.00001), but at four weeks, only in males (P < 0.05). It also mitigated reduced presence in target quadrant in both sexes at one week (P < 0.05), and in females at four weeks (P < 0.01). Pam3Cys prevented all rats at two days, and 60% of rats at 6 days after TBI, from entering the shock chamber (P < 0.01, P < 0.001 compared to TBI group) with no sex difference. Pam3Cys reduced TBI-induced cortical damage (70% decrease, P < 0.001) and neuronal death (75% decrease, P < 0.001) in the hippocampus. In short periods after mild TBI, impairment of spatial memory and Pam3Cys preventive effect are identical in male and female rats. However, at long-term periods, both effects are prominent in female rats. Modulation of TBI neuroinflammation seems to involve in Pam3Cys effects.