Paracetamol (acetaminophen) rescues cognitive decline, neuroinflammation and cytoskeletal alterations in a model of post-operative cognitive decline (POCD) in middle-aged rats

Abstract

Post-operative cognitive dysfunction (POCD) is a debilitating clinical phenomenon in elderly patients. Management of pain in elderly is complicated because analgesic opiates elicit major side effects. In contrast, paracetamol (acetaminophen) has shown analgesic efficacy, no impact on cognition, and its side effects are well tolerated. We investigated the efficacy of paracetamol, compared to the opioid analgesic buprenorphine, in a model of POCD by investigating cognitive decline, allodynia, peripheral and hippocampal cytokines levels, and hippocampal microtubule dynamics as a key modulator of synaptic plasticity. A POCD model was developed in middle-aged (MA) rats by inducing a tibia fracture via orthopaedic surgery. Control MA rats did not undergo any surgery and only received isoflurane anaesthesia. We demonstrated that cognitive decline and increased allodynia following surgery was prevented in paracetamol-treated animals, but not in animals which were exposed to anesthesia alone or underwent the surgery and received buprenorphine. Behavioral alterations were associated with different peripheral cytokine changes between buprenorphine and paracetamol treated animals. Buprenorphine showed no central effects, while paracetamol showed modulatory effects on hippocampal cytokines and markers of microtubule dynamics which were suggestive of neuroprotection. Our data provide the first experimental evidence corroborating the use of paracetamol as first-choice analgesic in POCD.

Figure 1

MA rats were impaired in the DNMTS task compared to YG controls. MA animals were impaired in the DNMTS task compared to YG controls at: (A) 48 h test-point overall performance; (B) 48 h test-point at the 6–10 s, 11–15 s to 21–25 s delay time bins; (C) 72 h test-point overall performance; (D) 72 h test-point at the 16–20 s and 21–25 s delay time bins; (E) Day 6 test-point overall performance; and (F) Day 6 test-point at the 11–15 s and 16–20 s delay time bins. Histograms represent Total % Correct response (the mean group performance across all delay lengths in the DNMTS task ± SEM), n = 4–6 per group. DNMTS trials were sorted by performance according to length of delay on individual trials and were grouped according to 5-s intervals (1–5, 6–10, 11–15, 16–20, 21–25, and 26–30) represented by line graphs (mean ± SEM). Two-way ANOVA followed by Fishers LSD analysis **p < 0.01, *p < 0.05 vs. YG controls.

Figure 2

Paracetamol (Par) treatment appears to recover POCD in the DNMTS. Results at 48 h test-point showed: (A) MA rats exposed to anaesthetic only or which underwent surgery (MA + Surgery Model) treated with Buprenorphine at 0.05 mg/kg, i.p. or 0.1 mg/kg, i.p. were impaired in the DNMTS task compared to MA controls. In contrast, MA animals treated with Par-75 mg/kg, s.c. or Par-150 mg/kg, s.c. were not impaired in the task compared to MA controls; (B) Examination of the Bup groups compared to control groups across delay length showed that surgery model groups treated with Bup-0.05 mg/kg or Bup-0.1 mg/kg were impaired at 6–10 s, 11–15 s, 16–20 s and 26–30 s time bins; (C) Examination of the Par groups compared to control groups across delay length showed that surgery model groups treated with Par-75 mg/kg or Par-150 mg/kg did not have any delay-induced impairment. Results at 72 h test-point showed: (D) No differences were observed between groups; (E) and (F) No group differences were observed following examination of performance across different delay lengths. Results at Day 7 test-point showed: (G) MA animals which underwent the surgery model treated with Bup-0.1 mg/kg were significantly impaired compared to MA Controls. Par treatment (75 mg/kg or 150 mg/kg) to surgery model animals prevented long lasting cognitive impairments; (H) MA + Surgery Model groups treated with Bup (0.05 mg/kg or 0.1 mg/kg) were impaired at delay time lengths 11–15 s to 21–25 s compared to MA control; (I) MA + Surgery Model group treated with Par-75 mg/kg were impaired at delay lengths 1–5 s and 16–20 s compared to MA control. Histograms represent Total % Correct response (the mean group performance across all delay lengths in the DNMTS task ± SEM), n = 5–11 per group. DNMTS trials were sorted by performance according to length of delay on individual trials and were grouped according to 5-s intervals (1–5, 6–10, 11–15, 16–20, 21–25, and 26–30) represented by line graphs (mean ± SEM). Two-way ANOVA followed by Fisher’s LSD analysis **p < 0.01, *p < 0.05 vs. MA control; ^##p < 0.01 vs. MA + Surgery Model (Par-150 mg/kg) group.

Figure 3

Buprenorphine (Bup) treatment precipitates negative effects on cognition following surgery. Animals which underwent the surgery model procedure and received buprenorphine (Bup, s.c.) treatment were impaired in their ability to complete DNMTS trials over the week of test days compared to animals treated with Paracetamol (Par, i.p.). Animals which did not complete the necessary 90 trials per test session where not included in the data analysis. Histograms represent the number of trials completed over all test sessions. One-way ANOVA followed by Fisher’s LSD analysis **p < 0.01, *p < 0.05 vs. MA control; ^##p < 0.01 vs. MA anaesthesia group.

Figure 4

Paracetamol (Par) has long-lasting analgesic efficacy in the cold plate allodynia test. Performance in the cold plate test was assessed on days 1 to 5 post-surgery/control procedure. MA surgery model groups treated with Bup-0.05 mg/kg or Bup-0.1 mg/kg (s.c.) displayed increased sensitivity compared to MA Controls on test days 3 and 5. Line graph represent mean performance over 5 test days (mean ± SEM), n = 11–12. Two-way ANOVA followed by Fisher’s LSD analysis **p < 0.01, *p < 0.05 vs. MA control.

Figure 5

Hippocampal α-tubulin PTMs are altered following exposure to anaesthesia or surgery. (A) Tyr-Tub/Glu-tub ratio is decreased in MA animals exposed to anaesthesia only and in the surgery model groups treated with Bup-0.05 mg/kg or Par-75 mg/kg compared to MA control. (B) Δ2/TOT-Tub ratio is increased in MA animals exposed to anaesthesia only and in the surgery model groups treated with Bup-0,05 mg/kg or Bup-0.1 mg.kg (s.c.) or Par-75 mg/kg or Par150mg/kg (i.p.) compared to MA control. Surgery animals treated with Bup-0.1 mg/kg had significantly higher Δ2/Tot-Tub ratio compared to MA animals exposed to anaesthesia only. Histograms represent data expressed as a percentage of the MA Control group (mean ± SEM), n = 10–12 per group. One-way ANOVA followed by Fisher’s LSD analysis ***p < 0.0001, **p < 0.01, *p < 0.05 vs. MA control; ^#p < 0.01, ^##p < 0.01 vs. MA + Anaesthesia group.