Biology subjects

Sharmin, D.

Publications and source records attributed to Sharmin, D..

6 recordsLinked to original sources

bioRxiv2024

Development of non-sedating antischistosomal benzodiazepines

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

pharmacology and toxicology↗

bioRxiv2023

An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism

Autism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of 5-containing GABAA receptors (5-GABAARs) SH-053-2F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based on in utero VPA exposure. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2F-R-CH3 could attenuate these changes. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2F-R-CH3. Despite sex differences, our findings indicate 5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

neuroscience↗

bioRxiv2023

Extrasynaptic localization is essential for α5GABAA receptor modulation of dopamine system function

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the 5, but not 1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds 5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting 5GABAARs from the extrasynaptic space to the synapse would prevent the effects of 5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated 5GABAARs and increased the proportion of synaptic 5GABAARs, without changing the overall expression of 5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of 5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic 5GABAARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present. Significance StatementDopamine activity is known to be altered in both psychosis patients and in animal models, with promising new antipsychotics restoring normal dopamine system function. One such drug is GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM). Interestingly, previous research has shown that a positive allosteric modulator of 1GABAARs (1-PAM) does not share this ability, even when directly given to the ventral hippocampus, a region known to modulate dopamine activity. One potential explanation for this difference we examined in this study is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. Determining the mechanism of this differential efficacy could lead to the refinement of antipsychotic treatment and improve patient outcomes overall.

neuroscience↗

bioRxiv2022

Positive allosteric modulation of α5-GABA A Receptor in the 5XFAD mouse model has cognitive and neurotrophic benefits

INTRODUCTIONReduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimers disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through 5-GABA-A receptors (5-GABAA-R). 5-GABAAR positive allosteric modulation (5-PAM) has procognitive and neurotrophic effects in stress and aging models. METHODSWe tested whether 5-PAM (GL-II-73) could reverse cognitive deficits and neuronal spine loss in early and late stages of {beta}-amyloid deposition in the 5xFAD model (N=48/study; 50% female). RESULTSAcute or chronic administration of GL-II-73 reversed spatial working memory in 5xFAD mice at 2 and 5 months of age. Chronic GL-II-73 treatment reversed 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite {beta}-amyloid accumulation. DISCUSSIONThese results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related {beta}-amyloid deposition. This suggests 5-PAM as a novel {beta}-amyloid-independent symptomatic therapeutic approach.

pharmacology and toxicology↗

bioRxiv2021

Positive modulation of cerebellar α6GABAA receptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice

BackgroundThe etiology of essential tremor (ET) remains unclear but may involve abnormal firing of Purkinje cells, which receive excitatory inputs from granule cells in the cerebellum. Since 6 subunit-containing GABAA receptors (6GABAARs) are abundantly expressed in granule cells, we validated a hypothesis that 6GABAAR-selective positive allosteric modulators (PAMs) are promising pharmacological interventions for ET therapy. MethodsEmploying the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of four 6GABAAR-selective PAMs, the pyrazoloquinolinones Compound 6 and LAU-463 and their respective deuterated derivatives. Propranolol, a clinical anti-tremor agent, was employed as positive control. To investigate the involvement of cerebellar 6GABAARs in the antitremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an 6GABAAR antagonist, was intracerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of wellbeing in rodents, was measured concurrently. ResultsHarmaline (10-30 mg/kg, s.c.) induced action tremor in ICR mice dose-dependently and markedly reduced their burrowing activity. Compound 6 (3 and 10 mg/kg, i.p.) significantly attenuated harmaline (20 mg/kg)-induced action tremor and burrowing activity impairment. Propranolol (20 mg/kg, i.p.) diminished tremor but failed to restore the burrowing activity in harmaline-treated mice. Importantly, both anti-tremor and burrowing activity restorative effects of Compound 6 (10 mg/kg, i.p.) was significantly reversed by co-administration of i.cb. furosemide at a dose (10 nmol/0.5 l) having no effect per se. All four 6GABAAR PAMs exhibited a similar therapeutic efficacy. Conclusion6GABAAR-selective PAMs significantly attenuated action tremor and restored physical well-being in a mouse model mimicking ET by acting in the cerebellum. Thus, 6GABAAR-selective PAMs may be potential therapeutic agents for ET.

pharmacology and toxicology↗

bioRxiv2021

Symptomatic and Disease-Modifying Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

Chronic stress is a risk factor for Major depressive disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at 2-GABAA-Rs contributes to anxiolytic properties, 5-GABAA-Rs to cognitive functions, and 1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing 2- and 5-GABAA-Rs activity, but devoid of 1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side effects. This study investigated the activity profiles and behavioral efficacy of two molecules enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the 2-, 3-, 5-GABAA-Rs and 5-containing GABAA-Rs, respectively, and have anti-depressant and pro-cognitive effects independently. Using unpredictable chronic mild stress (UCMS) in male and female mice (n=12/group), we show that acute and chronic administration of GL-RM combined the anti-depressant and pro-cognitive effects of each enantiomer, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined 2-, 3-, 5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.

neuroscience↗