Adenosine monophosphate–activated protein kinase activation is associated with suppression of NLRP3 inflammasome–mediated neuroinflammation in a weight-drop model of traumatic brain injury in Sprague–Dawley rats

Abstract

Background

Traumatic brain injury (TBI) disrupts adenosine monophosphate–activated protein kinase (AMPK) signaling, impairs energy homeostasis, activates inflammatory pathways, and triggers neuroinflammation. AMPK activators such as metformin (MET), quercetin (QUE), resveratrol (RES), cinnamaldehyde (CIN), and berberine (BER) exhibit anti-inflammatory and neuroprotective properties. However, their role in modulating the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome in TBI-induced neuroinflammation remains unclear. This study investigated the neuroprotective effects of AMPK activators in the weight-drop model of TBI, focusing on suppression of the NLRP3 inflammasome.

Methods

Rats received an intraperitoneal administration of AMPK activators—MET (100 mg/kg), QUE (15 mg/kg), RES (25 mg/kg), CIN (25 mg/kg), or BER (50 mg/kg)—from days −3 to 17. TBI was induced on day 1 using the weight-drop method (240 g from 1.5 m). Cognitive performance was evaluated using the novel object recognition test and Morris water maze. Neuroinflammatory markers, including nuclear factor kappa B (NF-κB), NLRP3, pro-caspase-1, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and microglial polarization markers (CD86 and CD206), were assessed using Western blotting and enzyme-linked immunosorbent assay (ELISA). Oxidative stress and histopathological changes were also examined.

Results

TBI resulted in cognitive impairment, oxidative stress, and neuronal damage; reduced p-AMPK/AMPK ratio; decreased CD206 levels; and elevated the levels of NF-κB, CD86, TNF-α, and NLRP3 inflammasome components (NLRP3, pro-caspase-1, and IL-1β). Pretreatment with AMPK activators significantly improved cognitive deficits, attenuated oxidative stress and neuroinflammation, restored p-AMPK/AMPK ratio, promoted anti-inflammatory effects, and suppressed NLRP3 inflammasome activation.

Conclusion

AMPK activators exhibited neuroprotection in TBI by improving cognition and regulating oxidative stress, microglial activation, and NLRP3-mediated neuroinflammation.