Biology subjects

Lipina, T. V.

Publications and source records attributed to Lipina, T. V..

3 recordsLinked to original sources

bioRxiv2024

Combination of Haloperidol with UNC9994, β-arrestin-biased analog of Aripiprazole, ameliorates schizophrenia-related phenotypes induced by NMDAR deficit in mice.

BackgroundGlutamatergic system dysfunction, particularly involving the N-methyl-D-aspartate receptor (NMDAR), contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical antipsychotic drug (APD), acts as a dopamine partial agonist and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia symptoms. Recently, an analog of aripiprazole - UNC9994 was developed. UNC9994 does not affect D2R-mediated Gi/o protein signaling but acts as a partial agonist for D2R/{beta}-arrestin interactions. Hence, our objective was to probe the effects of co-administrating haloperidol with UNC9994 in NMDAR mouse models of schizophrenia. MethodsNMDAR hypofunction was induced pharmacologically by acute injection of MK-801 (NMDAR pore blocker; 0.15 mg/kg) and genetically by knockdown of Grin1 gene expression in mice, which have a 90% reduction in NMDAR levels (Grin1-KD). After intraperitoneal injections of vehicle, haloperidol (0.15 mg/kg), UNC9994 (0.25 mg/kg) or their combination mice were tested in open field, Pre-Pulse inhibition (PPI), Y-maze and Puzzle box. ResultsOur findings indicate that low dose co-administration of UNC9994 and haloperidol reduces hyperactivity in MK-801-treated animals and in Grin1-KD mice. Furthermore, this dual administration effectively reverses PPI deficits, repetitive/rigid behavior in the Y-maze, and deficient executive function in the Puzzle box in both animal models. ConclusionsThe dual administration of haloperidol with UNC9994 at low doses represents a promising approach to ameliorate positive, negative, and cognitive symptoms of schizophrenia. Significance statementSchizophrenia is a devastating mental disorder and characterized by positive, negative, and cognitive symptoms. Cognitive and negative symptoms remain a focus of research dedicated to development of effective antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia symptoms. An analog of aripiprazole - UNC9994 was recently developed, which does not affect D2R-mediated Gi/o protein signaling but acts as a partial agonist for D2R/{beta}-arrestin interactions. Our pre-clinical findings on pharmacological (MK-801, 0.15 mg/kg) and genetic (Grin1-KD) mouse models of NMDAR deficiency showed that the dual administration of UNC9994 (0.25 mg/kg) with haloperidol (0.15 mg/kg) at low doses reduces hyperactivity, corrects prepulse inhibition (PPI) deficits, rigid behavior in the Y-maze, and deficient executive function in the Puzzle box. Further studies of the polypharmacy of UNC9994 with APDs is essential to facilitate translational studies in clinics.

pharmacology and toxicology↗

bioRxiv2023

Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants

Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also demonstrated rescue of nine VMAT2 variants that cause Brain Vesicular Monoamine Transport Disease (BVMTD). VMAT2 upregulation could be beneficial for disorders associated with reduced monoamine transmission, including mood disorders and BVMTD, a rare but often fatal condition caused by a lack of functional VMAT2. Our findings provide the first evidence that small molecules can upregulate VMAT2 and have potential therapeutic benefit for various neuropsychiatric conditions.

pharmacology and toxicology↗

bioRxiv2023

Lung lipid deposition in pneumonias of viral and non-viral aetiology

Pneumonia is an acute respiratory disease of varying etiology that has drawn much attention during the COVID-19 pandemic. Among the many thoroughly studied aspects of pneumonia, lipid metabolism has not been sufficiently addressed. Here, we investigated lipid deposition in the post mortem lung specimens of patients who died from COVID-19 and non-COVID-19 pneumonias. We used semi-thin sections and cryosections stained with Sudan III to visualize lipid droplet deposition within cells and in the extracellular space, most notably in small lung vessels. Electron microscopy analysis of the ultrathin sections was used to confirm the homogeneous structure of the droplets. Morphometric analysis revealed that the area of lipid deposition was increased in pneumonia compared to control lung tissue. Likewise, it was increased in the macroscopically inflamed vs. the macroscopically intact area of the same pneumonia lung. The lipid profiling by chromato-mass spectrometry revealed that lipid droplet accumulation in pneumonia was associated with a specific fatty acid content of the inflamed lung tissue. The gene expression analysis pointed to changes of lipid metabolism in the inflamed lung tissue compared to control lungs. Taken together, our data indicate a number of morphologic and metabolic changes associated with inflammation and common for pneumonias of different etiologies that likely contribute to pneumonia pathogenesis. Therefore, targeting lipid metabolism can be considered a new therapeutic strategy.

pathology↗