Neurotensin analog PD149163 attenuates endotoxemia-induced brain dysfunction and behavioural deficits via modulating CRP, GABAergic and NRF2 signalling pathways in mice: In vivo, in silico and network pharmacology analyses.

Endotoxemia-induced brain dysfunction is a complex neurological condition, with growing evidence underscoring the critical roles of neuroinflammation and oxidative stress in its pathogenesis. In this context, the current study was undertaken to evaluate the neuroprotective efficacy of the neuropeptide neurotensin analog PD149163 against endotoxemia-induced brain dysfunction and behavioural impairments in mice. Swiss-albino mice (female/08-weeks/25 ± 2.5 g) were divided into 6 groups: Group-I/control; Groups II and III were treated with 50 μg/kg BW and 100 μg/kg BW of PD149163, respectively, for 4 weeks. Groups IV-VI were injected with LPS (1 mg/kg BW; 5 days), followed by PD149163 exposure to Group-V/LPS + PDL (50 μg/kg BW) and Group-VI/LPS + PDH (100 μg/kg BW) for 4 weeks. Both the LPS and PD149163 were given intraperitoneally. LPS elevated circulatory proinflammatory (TNF-α/IL6), proapoptotic/CAS3 biomarkers and decreased anti-inflammatory/IL10, antiapoptotic/BCL2 proteins. Endotoxemia attenuated the brain oxidative defence via decreasing antioxidants (SOD/CAT) while increasing the pro-oxidants (LPO/LOOH). LPS-induced upregulated mCRP (plasma) and hsCRP (brain) cause blood-brain barrier disruption, leading to neuroinflammation and neurodegeneration, reflected in the histopathology of CA1/CA3/DG of the hippocampus and PVN of the hypothalamus. LPS-induced brain dysfunction impairs locomotor activity, induces anxiety and depression-like behaviours with cognitive impairment, while also diminishing neurotransmitter GABA release. Treatment with PDH for 4 weeks significantly improved the behavioural deficits and reversed biochemical and histopathological alterations. Our in silico/PPI analysis suggests PD149163 binds and inhibits KEAP1 (Kelch-like ECH-associated protein-1) and acts as Nrf2 (nuclear factor erythroid 2-related factor 2) activator. In conclusion, the current study demonstrates the neuroprotective effects of PD149163, potentially through modulation of Nrf2 pathway.