Delineating the molecular mechanisms of hippocampal neurotoxicity induced by chronic administration of synthetic cannabinoid AB-FUBINACA in mice.

Chronic use of synthetic cannabinoids (SCs) has been associated with cognitive and behavioural deficits and an increased risk of neuropsychiatric disorders. The underlying molecular and cellular mechanisms of the neurotoxic effects of long-term use of SCs have not been well investigated in the literature. Herein, we evaluated the in vivo effects of chronic administration of AB-FUBINACA on the hippocampus in mice. Our results revealed that the administration of AB-FUBINACA induced a significant impairment in recognition memory associated with histopathological changes in the hippocampus. These findings were found to be correlated with increased level of oxidative stress, neuroinflammation, and apoptosis markers, and reduced expression of brain-derived neurotrophic factor (BDNF), which plays an essential role in modulating synaptic plasticity integral for promoting learning and memory in the hippocampus. Additionally, we showed that AB-FUBINACA significantly decreased the expression of NR1, an important functional subunit of glutamate/NMDA receptors and closely implicated in the development of toxic psychosis. These findings shed light on the long-term neurotoxic effects of SCs on hippocampus and the underlying mechanisms of these effects. This study provided new targets for possible medical interventions to improve the treatment guidelines for SCs addiction.

The impact of chronic fentanyl administration on the cerebral cortex in mice: Molecular and histological effects.

PURPOSE: Fentanyl, a fully synthetic opioid, is widely used for severe pain management and has a huge abuse potential for its psychostimulant effects. Unlike other opioids, the neurotoxic effects of chronic fentanyl administration are still unclear. In particular, little is known about its effect on the cerebral cortex. The current study aims to test the chronic toxicity of fentanyl in the mice model. METHODS: Adult male Balb/c mice were chronically treated with low (0.05 mg/kg, i.p) and high (0.1 mg/kg, i.p) doses of fentanyl for 5 consecutive weeks, and various neurotoxic parameters, including apoptosis, oxidative stress, and neuroinflammatory response were assessed in the cortex. Potential histological as well as neurochemical changes were also evaluated. RESULTS: The results of this study show that chronic fentanyl administration induced intense levels of apoptosis, oxidative stress, and neuroinflammation in the cerebral cortex. These findings were found to be correlated with histopathological characteristics of neural degeneration and white matter injury. Moreover, fentanyl administration was found to reduce the expression of both NMDA receptor subunits and dopamine receptors and elevate the level of epidermal growth factor (EGF). CONCLUSION: Fentanyl administration induced neurotoxic effects in the mouse cerebral cortex that could be primarily mediated by the evoked oxidative-inflammatory response. The altered expression of NMDA receptors, dopamine receptors, and EGF suggests the pernicious effects of fentanyl addiction that may end in the development of toxic psychosis.

Chimeric antigen receptor T cells therapy in solid tumors.

Chimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target antigens than natural T cell surface receptor (TCR), resulting in tumor destruction. CAR-T is composed of an extracellular single-chain variable fragment (scFv) of antibody, which serves as the targeting moiety, hinge region, transmembrane spacer, and intracellular signaling domain(s). CAR-T has been developing in many generations, which differ according to costimulatory domains. CAR-T therapy has several limitations that reduce its wide availability in immunotherapy which we can summarize in antigen escape that shows either partial or complete loss of target antigen expression, so multiplexing CAR-T cells are promoted to enhance targeting of tumor profiles. In addition, the large diversity in the tumor microenvironment also plays a major role in limiting this kind of treatment. Therefore, engineered CAR-T cells can evoke immunostimulatory signals that rebalance the tumor microenvironment. Using CAR-T therapy in treating the solid tumor is mainly restricted by the difficulty of CAR-T cells infiltrating the tumor site, so local administration was developed to improve the quality of treatment. The most severe toxicity after CAR-T therapy is on-target/on-tumor toxicity, such as cytokine release syndrome (CRS). Another type of toxicity is on-target/off-tumor toxicity which originates from the binding of CAR-T cells to target antigen that has shared expression on normal cells leading to damage in healthy cells and organs. Toxicity management should become a focus of implementation to permit management beyond specialized centers.

Immunological, histopathological, and ultrastructural evidence of steroid-induced reactivation of chronic murine toxoplasmosis.

We developed a model of steroid-induced reactivation of chronic murine toxoplasmosis to mirror similar effects of steroids or other immunosuppressants in infected humans. Immunological, histopathological, and ultrastructural parameters were reported. Prior to steroid administration, mice were infected with 10 cysts of the Me49 strain of Toxoplasma gondii. Mice were treated with dexamethasone (DXM, 2.5 mg/kg/day in drinking water), alone or combined with Solu-Cortef (SOLU, 50 mg/kg by subcutaneous injection 3 times a week) for 7 weeks or left untreated as control. Histopathological changes and ultrastructural effects of steroids on the course of chronic toxoplasmosis were recorded. By electron microscopy, the brains of infected combined treated mice showed an increase in number of tachyzoites and bradyzoites, degeneration, and necrosis of neural cells and hydropic degeneration besides the observed rupture of toxoplasma cysts releasing free tachyzoites in brain tissue. DXM+SOLU-combined treatment also significantly increased mortality, mean brain cyst count as compared to infected untreated mice (P = .01 and). Moreover, 3/12 (25%) treated animals developed clinical signs of toxoplasmic encephalitis. This simple model of drug-induced reactivation of chronic toxoplasmosis permits investigation of host-parasite interaction and may be used for the evaluation of chemotherapeutics in immunocompromised infected patients.