Advances and Innovations in Dementia

Biography

Biography: Michael Entzeroth

Abstract

Statement of the Problem: Alzheimer’s disease is the most common form of dementia, affecting up to 70% of all people with dementia. A class of disease-non-modifying drugs, cholinesterase inhibitors, are commonly used to treat Alzheimer's disease (AD). These drugs increase glutamatergic transmission and improve memory, however, they do not protect from disease progression and lose efficacy over time. Other approaches such as the inhibition of beta amyloid and tau protein formation have so far failed to improve the symptoms or modify the progression of this disease. We report here on a new class of molecules, choline analogs that improve memory in rodents and non-human primates as well as demonstrated neuroprotection in cellular models. We investigated the effects of these candidates on glutamate release in the hippocampus. Methodology: Anaesthetized rats were either treated i.v. saline or CB8411 (50 µg/kg) or CB2233 (100 µg/kg). These subjects were then immediately scanned using a 9.4T ultra-high Bruker MRI, a 2.5x4x4 mm voxel in the hippocampus was scanned and glutamate levels were determined to determine baseline levels. After 30 min, the animals were treated with 1 mg/kg scopolamine. Scopolamine is an amnesiac agent that is known to diminish local glutamate levels. Findings: After administration of scopolamine, hippocampal glutamate levels decreased to approximately 89% of the pre-injection baseline levels. Both drug candidates, CB8411 and CB2233, attenuated the decrease in glutamate levels to about 94% of pre-injection baseline levels. Conclusion & Significance: CB8411 and CB2233 have previously been shown to increase memory in non-human primates. We demonstrate that this effect may be caused via modulation of glutamate in the hippocampus and subsequent enhancement of working memory. These candidates are suggested a new class of compounds that are likely to be useful in the symptomatic treatment of AD