sirolimus and Encephalitis

Inflammation is the focus of many studies on traumatic brain injury (TBI) treatment and outcomes improvement. Some studies have demonstrated that the inhibition of NOD-like receptor protein-3 (NLRP3) inflammasome activation is a potential strategy for TBI therapy. Mitophagy is thought to play a crucial role in pathological conditions of TBI. We hypothesize simultaneous mitophagy activation and NLRP3 inflammsome inhibition, plays preferable role in delaying the progression and nerve damage post-TBI. In this study, TBI-mice and oxygen and glucose deprivation (OGD)-induced primary cortical neurons were treated with MCC950 (a NLRP3 selective inhibitor) or Rapamycin (Rap, a mTOR inhibitor, stimulated autophagy and mitophagy). We evaluated the effects of Rap and NLRP3 inhibition on the neurological deficits, neurological damage, and inflammatory response, to determine if Rap further induced the neuroprotection of suppression of NLRP3 inflammasome activation in vivo and in vitro TBI-model. TBI induced NLRP3 inflammasome activation and mitochondrial dysfunction, including increased caspase-1 p20 expression, exacerbated the secretion of LDH, IL-1β and IL-18, and disorder of ATP, MMP, ROS and mitophagy (Pink1 and LC3 expression in mitochondria). NLRP3 inhibition and Rap attenuated the neurological damage and mitochondrial dysfunction, while combined treatment showed better neuroprotection compared with single treatment. Collectively, the data demonstrate that mitophagy and NLRP3 inflammasome have the interactivity, and Rap-induced mitophagy further enhances the neuroprotection of inhibition of NLRP3 inflammasome activation post-TBI. Our findings suggest that Rap-activated mitophagy combined with MCC950-induced NLRP3 inflammasome repression may be a potential strategy for TBI therapy.

Topics: Animals; Brain Injuries, Traumatic; Cerebral Cortex; Encephalitis; Furans; Heterocyclic Compounds, 4 or More Rings; Indenes; Inflammasomes; Male; Mice, Inbred C57BL; Mitophagy; Neurons; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Primary Cell Culture; Receptors, Cell Surface; Sirolimus; Sulfonamides; Sulfones

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.

Topics: Amygdala; Animals; Antidepressive Agents; Antioxidants; Encephalitis; Ketamine; Male; Oxidative Stress; Prefrontal Cortex; Rats, Wistar; Signal Transduction; Sirolimus

Epilepsy and other neurological deficits are common, disabling manifestations of the genetic disorder, tuberous sclerosis complex (TSC). Brain inflammation has been implicated in contributing to epileptogenesis in acquired epilepsy due to brain injury, but the potential role of inflammatory mechanisms in genetic epilepsies is relatively unexplored. In this study, we investigated activation of inflammatory mediators and tested the effects of anti-inflammatory treatment on epilepsy in the Tsc1-GFAP conditional knock-out mouse model of TSC (Tsc1(GFAP)CKO mice). Real-time quantitative RT-PCR, immunohistochemistry, and Western blotting demonstrated increased expression of specific cytokines and chemokines, particularly IL-1β and CXCL10, in the neocortex and hippocampus of Tsc1(GFAP)CKO mice, which was reversed by treatment with a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Double-labeling immunohistochemical studies indicated that the increased IL-1β was localized primarily to astrocytes. Importantly, the increase in inflammatory markers was also observed in astrocyte culture in vitro and at 2 weeks of age in Tsc1(GFAP)CKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures. Epicatechin-3-gallate, an inhibitor of IL-1β and CXCL10, at least partially reversed the elevated cytokine and chemokine levels, reduced seizure frequency, and prolonged survival of Tsc1(GFAP)CKO mice. These findings suggest that mTOR-mediated inflammatory mechanisms may be involved in epileptogenesis in the genetic epilepsy, TSC.

Topics: Animals; Anti-Inflammatory Agents; Catechin; Encephalitis; Hippocampus; Inflammation Mediators; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Neocortex; Neuroglia; Seizures; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins