Therefore, there is an urgent need for the identification of novel therapeutic targets. These drugs, however, provide marginal clinical benefit only and do not address the underlying causes of the disease. At present, all five drugs approved by the US Food and Drug Administration for the symptomatic treatment of AD are targeted towards these systems-including the acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine, and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. The significant loss of cells in these systems and the disruption of their molecular components results in a disturbed E/I balance in the AD brain, which could underlie the cognitive deficits that are characteristic of the condition. Dysfunction in the glutamatergic and cholinergic systems, which contribute to the excitatory aspect of the excitatory/inhibitory (E/I) balance, has long been implicated in AD pathogenesis. Aside from amyloid-β (Aβ) plaques and neurofibrillary tangles, which are the characteristic neuropathological hallmarks of AD, the dysfunction of several neurotransmitter systems, including the inhibitory γ-aminobutyric acid (GABA) system, has been associated with the development and progression of AD. ![]() In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD.Īlzheimer’s disease (AD) is a chronic neurodegenerative disorder associated with a progressive loss of neuronal and synaptic density, which clinically manifests as a gradual decline in memory and cognitive function. Treatment with α5IA restored Aβ 1-42-induced changes in the expression of α5GABAARs. Such changes in GABARs expression could potentially disrupt inhibitory neurotransmission and normal network activity. Furthermore, we observed an Aβ 1-42-induced increase in ambient GABA levels, as well as upregulated mRNA expression of the GABAAR α2,α5,β2/3 subunits and the GABABR R1 and R2 subunits. Treatment with 100 nM of α5IA reduced Aβ 1–42-induced cell loss by 23.8% ( p < 0.0001) after 6 h and by 17.3% after 5 days of treatment ( p < 0.0001). Mouse primary hippocampal cultures were exposed to either Aβ 1-42 alone, or α5IA alone, α5IA with Aβ 1–42 or vehicle alone, and changes in cell viability and mRNA expression of several GABAergic signaling components were assessed. This study aimed to characterize the effects of α5IA on amyloid beta (Aβ 1–42)-induced molecular and cellular changes. An inverse agonist of α5 subunit-containing GABAA receptors (α5GABAARs), 3-(5-Methylisoxazol-3-yl)-6-1,2,4-triazolophthalazine (α5IA) has cognition-enhancing properties. Increasing evidence suggests a remodeling of the GABAergic system in AD, which might represent an important therapeutic target. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which no cognition-restoring therapies exist.
0 Comments
Leave a Reply. |