The α5-GABAAR inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aβ

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

“…In addition, curcumin was also effective on the learning and memory deficits in rats caused by sodium arsenite, suggesting that PI3K/Akt/GSK3β signaling stimulated by BDNF is involved in the effects of curcumin [ 28 ]. Interestingly, hippocampal Aβ accumulation and cognitive deficits in contextual fear conditioning in mice after repeated peripheral administration of LPS was observed, and the cognitive deficits associated with the increased hippocampal Aβ was reversed by a benzodiazepine agonist MRK-016 [ 29 ]. In their system, mRNA levels of BDNF decreased by LPS injections were also restored by MRK-016 [ 29 ].…”

“…Interestingly, hippocampal Aβ accumulation and cognitive deficits in contextual fear conditioning in mice after repeated peripheral administration of LPS was observed, and the cognitive deficits associated with the increased hippocampal Aβ was reversed by a benzodiazepine agonist MRK-016 [ 29 ]. In their system, mRNA levels of BDNF decreased by LPS injections were also restored by MRK-016 [ 29 ]. Furthermore, effect of combined zinc and folic acid administration in a depression model established by chronic mild unpredictable stress was also studied [ 30 ].…”

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update

“…It was able to enhance cognitive performance in the delayed matching-to-position version of the Morris water maze and was not proconvulsant or anxiogenic. MRK-016 has also been shown to protect against lipopolysaccharide-induced deficits in memory acquisition and consolidation and restore the behavioral expression of fear in lipopolysaccharide-treated animals, an effect that may be attributed to increased brain-derived neurotrophic factor mRNA expression. , Finally, MRK-016 has antidepressant-like activity in a variety of preclinical assays. − …”

“…MRK-016 has also been shown to protect against lipopolysaccharide-induced deficits in memory acquisition and consolidation and restore the behavioral expression of fear in lipopolysaccharide-treated animals, an effect that may be attributed to increased brain-derived neurotrophic factor mRNA expression. 122,123 Finally, MRK-016 has antidepressant-like activity in a variety of preclinical assays. 124−126 Although MRK-016 had a short half-life in preclinical species, it had a lower rate of in vitro turnover in human hepatocytes and this translated into a half-life in man of 3.5 h. On the basis of plasma drug concentrations and the occupancy EC 50 value in rhesus monkey (21 ng/mL), the maximum tolerated dose of 5 mg in young healthy controls was estimated to correspond to 75% GABA A R occupancy.…”

Selective Modulation of α5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer’s Disease

“…Following the development of this compound by MSD, several other nootropic drugs (α5 sub-type selective NAMs) have been developed (e.g., RO4938581;Ballard et al, 2009). Many of these studies reported an impressive pharmacological profile of this compounds and their potential as cognitive enhancers without CNS-mediated adverse effects (Chambers et al, 2003;Collinson et al, 2006;Dawson et al, 2006;Ballard et al, 2009;Braudeau et al, 2011;Martinez-Cue et al, 2014;Duchon et al, 2019;Eimerbrink et al, 2019). These studies were initially implemented in rodent models, and unfortunately, these results were not reproducible in human subjects/patients to the same extent.…”