Implication of M2 macrophage on NLRP3 inflammasome signaling in mediating the neuroprotective effect of Canagliflozin against methotrexate-induced cognitive impairment.

Methotrexate (MTX), a chemotherapeutic antimetabolite, has been linked to cognitive impairment in cancer patients. MTX-induced metabolic pathway disruption may result in decreased antioxidant activity and increased oxidative stress, influencing hippocampal neurogenesis and microglial activation. Nuclear factor-kappa B (NF-κB), an oxidative stress byproduct, has been linked to MTX toxicity via the activation of NLRP3 inflammasome signaling. Macrophage activation and polarization plays an important role in tissue injury. This differentiation may be mediated via either the Toll-like receptor 4 (TLR4) or NLRP3 inflammasome. Interestingly, Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor has been recently reported to exert anti-inflammatory effects by modulating macrophage polarization balance. This study aimed to investigate CANA's protective effect against MTX-induced cognitive impairment, highlighting the possible involvement of TLR4/ NF-κB crosstalk with NLRP3 inflammasome activation and macrophage polarization. Forty-eight Male Wistar rats were divided into 4 groups; (1) received saline orally for 30 days and intravenously on days 8 and 15. (2) received Canagliflozin (CANA; 20 mg/kg/day; p.o.) for 30 days. (3) received MTX (75 mg/kg, i.v.) on day 8 and 15, then they were injected with four i.p. injections of leucovorin (LCV): the first dose was 6 mg/ kg after 18 h, and the remaining doses were 3 mg/kg after 26, 42, and 50 h of MTX administration. (4) received MTX and LCV as in group 3 in addition to CANA as in group 2. MTX-treated rats showed cognitive deficits in spatial and learning memory as evidenced in the novel object recognition and Morris water maze tests. MTX exerted an oxidative effect which was evident by the increase in MDA and decline in SOD, GSH and GPx. Moreover, it exerted an inflammatory effect via elevated caspase-1, IL-1ß and IL-8. CANA treatment restored cognitive ability, reduced MTX-induced oxidative stress and neuroinflammation via attenuation of TLR4/NF-κB/NLRP3 signaling, and rebalanced macrophage polarization by promoting the M2 phenotype. Hence, targeting molecular mechanisms manipulating macrophage polarization may offer novel neuroprotective strategies for preventing or treating MTX-induced immune modulation and its detrimental sequel.

Paroxetine ameliorates changes in hippocampal energy metabolism in chronic mild stress-exposed rats.

The molecular mechanisms underlying stress-induced depression have not been fully outlined. Hence, the current study aimed at testing the link between behavioral changes in chronic mild stress (CMS) model and changes in hippocampal energy metabolism and the role of paroxetine (PAROX) in ameliorating these changes. Male Wistar rats were divided into three groups: vehicle control, CMS-exposed rats, and CMS-exposed rats receiving PAROX (10 mg/kg/day intraperitoneally). Sucrose preference, open-field, and forced swimming tests were carried out. Corticosterone (CORT) was measured in serum, while adenosine triphosphate and its metabolites, cytosolic cytochrome-c (Cyt-c), caspase-3 (Casp-3), as well as nitric oxide metabolites (NOx) were measured in hippocampal tissue homogenates. CMS-exposed rats showed a decrease in sucrose preference as well as body weight compared to control, which was reversed by PAROX. The latter further ameliorated the CMS-induced elevation of CORT in serum (91.71±1.77 ng/mL vs 124.5±4.44 ng/mL, P<0.001) as well as the changes in adenos-ine triphosphate/adenosine diphosphate (3.76±0.02 nmol/mg protein vs 1.07±0.01 nmol/mg protein, P<0.001). Furthermore, PAROX reduced the expression of Cyt-c and Casp-3, as well as restoring NOx levels. This study highlights the role of PAROX in reversing depressive behavior associated with stress-induced apoptosis and changes in hippocampal energy metabolism in the CMS model of depression.