Maneuver of EC immunization with a protein antigen that induces suppressor cells to inhibit inflammatory responses may become an attractive, noninvasive, needle-free therapeutic method for different clinical situations.

Treatment of tremors, such as in essential tremor (ET) and Parkinson’s disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and have safety liabilities. The aim of this study was a search for GABA-A subunit-specific tremorolytics using different tremor-generating mechanisms. Two selective positive allosteric modulators (PAMs) were tested. Zolpidem, targeting GABA-A α1, was not effective in models of harmaline-induced ET, pimozide- or tetrabenazine-induced tremulous jaw movements (TJMs), while the novel GABA-A α2/3 selective MP-III-024 significantly reduced both the harmaline-induced ET tremor and pimozide-induced TJMs. While zolpidem decreased the locomotor activity of the rats, MP-III-024 produced small increases. These results provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by α2/3 but not α1 containing GABA-A receptors. Tremor suppression by MP-III-024 provides a compelling reason to consider selective PAMs targeting α2/3-containing GABA-A receptors as novel therapeutic drug targets for ET and PD-associated tremor. The possibility of the improved tolerability and safety of this mechanism over non-selective GABA potentiation provides an additional rationale to further pursue the selective α2/3 hypothesis.

Background Previous studies showed that natural killer (NK) cells mediate contact hypersensitivity (CHS) reaction. Many reports are showing that obesity promotes several inflammatory diseases. It was shown that diet‐induced obesity (DIO) aggravates classical T cell–mediated CHS in mice. Objectives To determine whether the high‐fat diet (HFD)–induced obesity modulates antigen‐specific NK cell–mediated response. Methods We evaluated the effect of DIO on NK cell–mediated CHS reaction using a model of dinitrofluorobenzene (DNFB)–induced CHS in Rag1−/− mice. Results Rag1−/− mice fed HFD for 8 but not for 4 weeks developed aggravated CHS reaction determined by ear swelling measurement when compared to animals kept on normal diet (ND) prior to DNFB sensitization. The obese Rag1−/− mice presented the adipose tissue inflammation. Furthermore, in vitro analysis showed that feeding with HFD significantly increases interferon γ (IFN‐γ) and interleukin (IL)‐12p70 and decreases adiponectin concentration in liver mononuclear cell (LMNC) culture supernatants. The flow cytometry analysis of LMNC revealed that HFD treatment prior to DNFB sensitization increases the percentage of NK1.1+IFN‐γ+ cell population and affects the development and maturation of NK1.1+ cells. Conclusions In summary, current results suggest that the DIO significantly modulates the local and systemic inflammatory response, contributing to exacerbation of the CHS response mediated by liver NK cells.

Tom 68 2019 Numer 3 (324) Strony 375-387Przedstawiona praca ma na celu przybliżenie niektórych modeli myszy z niedoborami odporności, z uwzględnieniem genetyki, charakterystyki fenotypowej oraz ich zastosowania w badaniach naukowych.