Biology subjects

Bruszt, N.

Publications and source records attributed to Bruszt, N..

2 recordsLinked to original sources

bioRxiv2023

Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats

Combination treatments based on pharmacological interactions at 7 nAChRs are promising therapeutic approaches for neurocognitive disorders (NCDs). Memantine, an already approved medication in some NCDs, may not only act as an antagonist of the glutamatergic NMDA receptors (NMDAR) but also serve as an antagonist of the cholinergic 7 nAChRs. Here we set out to utilize a combination treatment regime with an 7 nAChR-selective agonist (PHA-543613) and a novel proprietary 7 nAChR ligand with marked positive allosteric modulator (PAM) activity (CompoundX). The cognitive efficacy of combination treatments was tested in a naturally aged rat model. Naturally aged rats showed marked cognitive decline in the novel object recognition (NOR) test, and they displayed pathological changes at the molecular level in terms of various inflammatory markers. In addition, aged rats also exhibited cholinergic changes such as mRNA upregulation of 7 nAChRs. Memantine-PHA-543613 and memantine-CompoundX combination treatments successfully alleviated the age-related decline of recognition memory of rats by exceeding the null-effects of the corresponding subtherapeutic levels of monotreatments. Results indicate a positive interaction between memantine and 7-nAChR agonists and PAMs, which reflects a prominent role of 7 nAChRs in the cognitive enhancement of combination treatments especially in age-related cognitive decline. Moreover, the putative direct action of memantine on 7 nAChRs may also contribute to the observed synergistic interaction between memantine and other selective 7 nAChR compounds.

pharmacology and toxicology↗

bioRxiv2019

Long-term persistence of cognitive impairment following repetitive mild traumatic brain injury in rats is not associated with common histopathological or molecular biomarkers

Repetitive mild traumatic brain injuries (TBI) impair cognitive abilities and increase risk of neurodegenerative disorders in humans. We developed two repetitive mild TBI models in rats with different time intervals between successive weight-drop injuries, and assessed cognitive performance and biomarker profiles. Rats were subjected to repetitive Sham (no injury), single mild (mTBI), repetitive mild (rmTBI - 5 hits, 24 h apart), rapid repetitive mild (rapTBI - 5 hits, 5 min apart) and single severe (sTBI) TBI. We assessed cognitive performance 2 and 8 weeks after TBI in the novel object recognition test (NOR), and 6-7 weeks after TBI in the water maze (MWM). Acute immunohistochemical markers were checked 24 h after TBI, and blood biomarkers were measured with ELISA 8 weeks after TBI. In the NOR, both rmTBI and rapTBI showed poor performance at 2 weeks post-injury. At 8 weeks post-injury, the rmTBI group still performed worse than the Sham and mTBI groups, while the rapTBI group recovered. In the MWM, the rapTBI group performed worse than Sham and mTBI. Acute APP and RMO-14 immunohistochemistry showed axonal injury at the pontomedullary junction in the sTBI, but not in other groups. ELISA showed increased serum GFAP levels 8 weeks after sTBI, while no differences were found between the injury groups in the levels of phosphorylated-tau and S100{beta}. Results suggest that the rmTBI protocol is the most suitable model for testing cognitive impairment after mild repetitive head injuries. The lack of common biomarkers suggests novel unknown underlying mechanisms of rmTBI.

neuroscience↗