Selective TLR4 antagonism prevents and reverses morphine-induced persistent post-operative cognitive dysfunction, dysregulation of synaptic elements, and impaired BDNF signaling in aged male rats.

Perioperative neurocognitive disorders (PND) are characterized by confusion, difficulty with executive function, and episodic memory impairment in the hours to months following a surgical procedure. Post-operative cognitive dysfunction (POCD) represents such impairments that last beyond 30-days post-surgery and is associated with increased risk of comorbidities, progression to dementia, and higher mortality. While it is clear that neuroinflammation plays a key role in PND development, what factors underlie shorter self-resolving versus persistent PNDs remains unclear. We have previously shown that post-operative morphine treatment extends POCD from 4-days (without morphine) to at least 8-weeks (with morphine) in aged male rats, and that this effect is likely dependent on morphine's pro-inflammatory capabilities via activation of toll-like receptor 4 (TLR4). Here, we extend these findings to show that TLR4 blockade, using the selective TLR4 antagonist LPS-RS Ultrapure, ameliorates morphine-induced POCD in aged male rats. Using either a single central pre-operative treatment and a 1-week post-operative central treatment regimen, we demonstrate that TLR4 antagonism 1) prevents and reverses the long-term memory impairment associated with surgery and morphine-treatment, 2) ameliorates morphine-induced dysregulation of the post-synaptic proteins post-synaptic density 95 and synaptopodin, 3) mitigates reductions in mBDNF, and 4) prevents decreased activation of the BDNF receptor TrkB, all at 4-weeks post-surgery. We also reveal that LPS-RS likely exerts its beneficial effects by preventing endogenous danger signal HMGB1 from activating TLR4, rather than by blocking continuous activation by morphine or its metabolites. These findings suggest TLR4 as a promising therapeutic target to prevent or treat PNDs. SIGNIFICANCE STATEMENT: With humans living longer than ever, it is crucial that we identify mechanisms which contribute to aging-related vulnerability to cognitive impairment. Here, we show that the innate immune receptor TLR4 is a key mediator of cognitive dysfunction in aged rodents following surgery and post-operative morphine treatment. Inhibition of TLR4 both prevented and reversed surgery+morphine-associated memory impairment, dysregulation of synaptic elements, and reduced BDNF signaling. Together, these findings implicate TLR4 in the development of post-operative cognitive dysfunction, providing mechanistic insight and novel therapeutic targets for the treatment of cognitive impairments following immune challenges such as surgery in older individuals.