Biology subjects

Knutson, D. E.

Publications and source records attributed to Knutson, D. E..

3 recordsLinked to original sources

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↗

bioRxiv2020

Chronic administration of a positive allosteric modulator at the alpha5-GABAA receptor reverses age-related dendritic shrinkage

Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting {beta}-amyloid in Alzheimers disease, for example. However, {beta}-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the 5-containing GABA-A receptors improve cognitive performances, and that these 5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the 5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an 5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the 5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the 5-PAM.

neuroscience↗

bioRxiv2018

Potential combined pro-cognitive, anxiolytic and antidepressant properties of novel GABAA receptor positive modulators with preferential efficacy at the α5-subunit

Altered {gamma}-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging and neurodegenerative disorders, and reduced function of somatostatin - expressing GABA interneurons is associated with both mood and cognitive symptoms. Somatostatin-neurons signal in part through 5-subunit containing GABAA receptors (5-GABAA-Rs) which are localized in brain regions implicated in emotion and cognition. We hypothesize that enhancing 5-GABAA-R activity has therapeutic potential for both mood and cognitive symptoms in stress-based and aging rodent models.\n\nWe synthesized four novel imidazobenzodiazepine (IBZD) amide ligands, tested them for positive allosteric modulation at 5-GABAA-R (5-PAM), pharmacokinetic properties, and for anxiolytic and antidepressant activities in adult mice. Pro-cognitive activity was tested in adult mice submitted to chronic stress and in old mice. Diazepam (DZP), with broad PAM activity at GABAA-Rs, was used as a control.\n\nThree novel IBZD amide ligands (GL-II-73, GL-II-74 and GL-II-75) demonstrated adequate brain penetration, affinity and 5-PAM activity, and metabolic stability for in vivo studies. GL-II-73/74/75 showed significant anxiolytic and antidepressant efficacies in adult mice. GL-II-73 and GL-II-75 significantly reversed cognitive deficits induced by stress or occurring throughout normal aging. This activity was maintained after sub-chronic administration for GL-II-73. In contrast DZP displayed anxiolytic but no antidepressant or pro-cognitive activities.\n\nWe demonstrate for the first time the potential for combined anxiolytic, antidepressant and pro-cognitive therapeutic, mediated by newly designed IBDZ amide ligands with efficacy at 5-GABAA-Rs. These results suggest a novel therapeutic approach targeting both mood and cognitive symptoms in depression and/or aging.

pharmacology and toxicology↗