Researchers at the Center for Addiction and Mental Health (CAMH) in Toronto, led by Dr Etienne Sibille, are developing a new type of therapy that could reverse everyday memory lapses.
GlobalData’s Pharmaceutical Technology reports: “Currently, there are a few types of medication used for treating cognitive impairments in Alzheimer’s disease. These include cholinesterase inhibitors, which stop the cholinesterase enzyme from clearing out acetylcholine (important for memory functioning) from the synapses. There is also memantine, which is thought to prevent excessive levels of glutamate from harming the brain.
“This new therapy holds potential for Alzheimer’s disease. However, it could also be used to forestall the memory symptoms associated with normal ageing and depression. Currently in the late pre-clinical stage, they target a completely different mechanism.”
Dr Etienne Sibille, Deputy Director of the Campbell Family Mental Health Research Institute at CAMH, told GlobalData’s Pharmaceutical Technology: “Cognitive deficits have not been considered an endpoint for drug development in psychiatric disorders until recently, hence little effort was devoted to it.
“In Alzheimer’s, drugs that block acetyl cholinesterase and increase acetylcholine have low efficacy and most of the attention on new drug development has been on amyloid-related pathologies.”
The new molecules work by binding to and activating GABA receptors in the brain. GABA, a major inhibitory neurotransmitter, is believed to play an important role in memory – it slows down the rate at which neurons fire, preventing overstimulation. Altered levels of GABA have been reported in depression, anxiety, neurodegenerative disorders such as Alzheimer’s, and normal ageing.
Sibille continues: “These novel molecules increase the function of a specific type of inhibitory GABAergic interneurons, which are deficient in many brain disorders.
The drug is a version of benzodiazepine, a class of anti-anxiety medicines that have broad effects on the GABA system (the two most famous examples are Xanax and Valium). However, the new molecules act in a more finely tuned manner, targeting GABA receptors in the parts of the brain that are most involved in cognition.
Sibille adds: “So far we have shown that our novel compounds enter the brain and are safe. At the behavioral level they display pro-cognitive effects in stress and aged mouse models, in addition to reducing anxiety and potentially depression.
“We are now performing late pre-clinical studies so that we can submit an Innovative New Drug (IND) application to the US FDA to begin human studies. If all works out in terms of funding, we could start a human safety study in two years.”
According to GlobalData’s Pharmaceutical Technology: “As well as learning and memory, the drug could enhance other areas of cognition, including executive function, decision making and planning. While it wouldn’t improve these areas in healthy individuals – and hence couldn’t be used as a ‘smart drug’ – it could play an important role in treating impairments.
“This may be particularly useful within depression, as patients in remission with cognitive symptoms are often the most likely to relapse.
“While all these experiments are in the early stages, research into the topic is generating excitement. New classes of drugs for cognitive deficits – a previously underlooked area – may not be too far afield.”