作者: Martínez-Serrano, Irene ; Mas, Sergi ; Martínez-Pinteño, Albert ; Parellada, Eduard ; Gassó, Patricia ; Prohens, Llucía ; Morén, Constanza ; Madero, Santiago ; Rodríguez, Natalia ; Olivares-Berjaga, David

Current treatment for schizophrenia (SZ) ameliorates the positive symptoms, but is inefficient in treating the negative and cognitive symptoms. The SZ glutamatergic dysfunction hypothesis has opened new avenues in the development of novel drugs targeting the glutamate storm, an inducer of progressive neuropathological changes. Positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), reduce the presynaptic release of glutamate, which has previously been demonstrated to attenuate glutamate- and dopamine-induced apoptosis in human neuroblastoma cell cultures. We hypothesised that JNJ treatment would modify the brain levels of apoptotic proteins in a mouse model of ketamine (KET)-induced schizophrenia. We analysed the levels of proapoptotic (caspase-3 and Bax) and antiapoptotic (Bcl-2) proteins by western blot in the prefrontal cortex and hippocampus of JNJ-treated mice. JNJ attenuated apoptosis in the brain by partially restoring the levels of the antiapoptotic Bcl-2 protein, which is significantly reduced in animals exposed to KET. Additionally, a significant inverse correlation was observed between proapoptotic protein levels and behavioural deficits in the mice. Our findings suggest that JNJ may attenuate brain apoptosis in vivo, as previously described in cell cultures, providing a link between neuropathological deficits and SZ symptomatology.

2023-12-15·Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy

Spectroscopic and optical properties of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one as a component of herbicides.

Article

作者: Janczak, Jan ; Dymińska, Lucyna ; Lisiecki, Radosław ; Hanuza, Jerzy ; Ptak, Maciej

The herbicides azafenidin [(2-(2,4-dichloro-5-prop-2-ynoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-one)] and flumetsulam [(N-(2,6-difluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide)] were subjected to IR, Raman, UV-Vis and emission studies. As triazolopyridine is the most prominent and active component of these herbicides, this molecule was characterised by XRD studies, FTIR, Raman, UV-Vis and emission spectra. The experimental data were compared to the results of the DFT quantum chemical calculations carried out for its optimised structure, IR intensities and Raman activities, HOMO-LUMO transitions, and energies of the singlet and triplet states. The characteristics for triazolopyridine quantities were used in the analysis of the studied herbicides.

2023-02-01·Biomedicine & Pharmacotherapy

Early treatment with JNJ-46356479, a mGluR2 modulator, improves behavioral and neuropathological deficits in a postnatal ketamine mouse model of schizophrenia

Article

作者: Gómez, M ; García-Rizo, C ; Gassó, P ; Prohens, L ; Rodríguez, N ; Parellada, E ; Olivares, D ; Martínez-Pinteño, A ; Mas, S ; Morén, C ; Madero, S

Positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), may mitigate the glutamate storm during the early stages of schizophrenia (SZ), which could be especially useful in the treatment of cognitive and negative symptoms. We evaluated the efficacy of early treatment with JNJ or clozapine (CLZ) in reversing behavioral and neuropathological deficits induced in a postnatal ketamine (KET) mouse model of SZ. Mice exposed to KET (30 mg/kg) on postnatal days (PND) 7, 9, and 11 received JNJ or CLZ (10 mg/kg) daily in the adolescent period (PND 35-60). Mice exposed to KET did not show the expected preference for a novel object or for social novelty, but they recovered this preference with JNJ treatment. Similarly, KET group did not show the expected dishabituation in the fifth trial, but mice treated with JNJ or CLZ recovered an interest in the novel animal. Neuronal immunoreactivity also differed between treatment groups with mice exposed to KET showing a reduction in parvalbumin positive cells in the prefrontal cortex and decreased c-Fos expression in the hippocampus, which was normalized with the pharmacological treatment. JNJ-46356479 treatment in early stages may help improve the cognitive and negative symptoms, as well as certain neuropathological deficits, and may even obtain a better response than CLZ treatment. This may have relevant clinical translational applications since early treatment with mGluR2 modulators that inhibit glutamate release at the onset of critical phases of SZ may prevent or slow down the clinical deterioration of the disease.

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适应症	最高研发状态	国家/地区	公司	日期
中枢神经系统疾病	临床前	比利时	Janssen Pharmaceutica NV	2016-09-09
中枢神经系统疾病	临床前	西班牙	Janssen-Cilag SA	2016-09-09
精神分裂症	临床前	美国	Johnson & Johnson	-