Inflammasome activation in peritumoral astrocytes is a key player in breast cancer brain metastasis development.

Inflammasomes, primarily responsible for the activation of IL-1ß, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1ß to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1ß in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1ß prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1ß expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1ß. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1ß release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases.

Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinical studies. In this study, the synthesis of these KYNA derivatives and their evaluation with divergent molecular characteristics are presented together with their most typical effects on the monosynaptic transmission in CA1 region of the hippocampus of the rat. Their effects on the basic neuronal activity (on the field excitatory postsynaptic potentials: fEPSP) were studied in in vitro hippocampal slices in 1 and 200 µM concentrations. KYNA and its derivative 4 in both 1 and 200 µM concentrations proved to be inhibitory, while derivative 8 only in 200 µM decreased the amplitudes of fEPSPs. Derivative 5 facilitated the fEPSPs in 200 µM concentration. This is the first comparative study which evaluates the structural and functional differences of formerly and newly developed KYNA analogs. Considerations on possible relations between molecular structures and their physiological effects are presented.