Piracetam Attenuates LPS-Induced Neuroinflammation and Cognitive Impairment in Rats

Abstract

The present study was performed to investigate the effect of piracetam on neuroinflammation induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior. Neuroinflammation was induced by a single dose of LPS solution infused into each of the lateral cerebral ventricles in concentrations of 1 μg/μl, at a rate of 1 μl/min over a 5-min period, with a 5-min waiting period between the two infusions. Piracetam in doses of 50, 100, and 200 mg/kg i.p. was administered 30 min before LPS infusion and continued for 9 days. On ninth day, the behavioral test for memory and anxiety was done followed by blood collection and microdissection of the hippocampus (HIP) and prefrontal cortex brain regions. Piracetam attenuated the LPS-induced decrease in coping strategy to novel environment indicating anxiolytic activity. It also reversed the LPS-induced changes in the known arm and novel arm entries in the Y-maze test indicating amelioration of spatial memory impairment. Further, piracetam moderated LPS-induced decrease in the mitochondrial complex enzyme activities (I, II, IV, and V) and mitochondrial membrane potential. It ameliorated changes in hippocampal lipid peroxidation and nitrite levels including the activity of superoxide dismutase. Piracetam region specifically ameliorated LPS-induced increase in the level of IL-6 in HIP indicating anti-neuroinflammatory effect. Further, piracetam reduced HIP Aβ (1-40) and increased blood Aβ level suggesting efflux of Aβ from HIP to blood. Therefore, the present study indicates preclinical evidence for the use of piracetam in the treatment of neuroinflammatory disorders.

Keywords: Amyloid beta; Cognition; Lipopolysaccharide; Mitochondrial dysfunction; Neuroinflammation; Piracetam.

Fig. 1

Experiment design indicating LPS infusion and piracetam treatment

Fig. 2

The effect of piracetam (50, 100, and 200 mg/kg) on LPS-induced changes in a number of crossings in the open field test. b Known arm entries (%) and c novel arm entries (%) in Y-maze to determine altered arm discrimination (spatial recognition memory). d Coping behavior to a novel environment. e Curiosity trial 1 and f curiosity trial 2 to determine curiosity behavior. All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100. All results were analyzed using one-way ANOVA followed by Student Newman–Keuls test

Fig. 3

Effect of piracetam (50, 100, and 200 mg/kg) on LPS-induced changes in mitochondrial electron transport chain enzyme activity in different brain regions: a complex I activity, b complex II activity, c complex IV activity, and d complex V activity. All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100. All results were analyzed using one-way ANOVA followed by Student Newman–Keuls test

Fig. 4

Effect of piracetam (50, 100, and 200 mg/kg) on LPS-induced alterations in the mitochondrial membrane potential in HIP and PFC. All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100. All results were analyzed using one-way ANOVA followed by Student Newman–Keuls test

Fig. 5

Effect of piracetam (50, 100, and 200 mg/kg) on mitochondrial oxidative stress: a SOD level, b NO level, and c LPO level. All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100. All results were analyzed using one-way ANOVA followed by Student Newman–Keuls test

Fig. 6

Effect of piracetam (50, 100, and 200 mg/kg) on LPS-induced increased IL-6 level in HIP and PFC. The blots are representative of IL-6 (a) in HIP and PFC. The results in the histogram are expressed as the ratio of the relative intensity of levels of protein expression of IL-6 to β-Actin (b). All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100 (One-way ANOVA followed by Student Newman–Keuls test)

Fig. 7

Effect of piracetam (50, 100, and 200 mg/kg) on LPS-induced increased Aβ (1–40) level in HIP and PFC. The blots are representative of Aβ (a) in HIP and PFC. The results in the histogram are expressed as the ratio of the relative intensity of levels of protein expression of Aβ to β-Actin (b). All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100 (One-way ANOVA followed by Student Newman–Keuls test)

Fig. 8

Effect of piracetam (50, 100, and 200 mg/kg) on increased efflux of Aβ (1–40) level from brain regions to blood. The blots are representative of Aβ (a) in plasma. The results in the histogram are expressed as the ratio of the relative intensity of levels of protein expression of Aβ to β-Actin (b). All Values are Mean ± SEM. ^a p < 0.05 compared to control, ^b p < 0.05 compared to LPS, ^c p < 0.05 compared to P-50, ^d p < 0.05 compared to P-100 (One-way ANOVA followed by Student Newman–Keuls test)