Drug Development

The drugs fighting memory loss

Researchers in Toronto have developed an experimental drug that appears to renew the underlying brain impairments causing memory loss, fuelling hopes that a treatment for cognitive decline linked to depression and aging may be on the horizon. Abi Millar takes a look.

Medicines for memory loss are hard to come by. For people who want to keep their minds sharp into old age, the usual wisdom is simply to adopt a healthy lifestyle – eat a balanced diet, exercise, reduce stress levels and maybe do the occasional crossword. You can’t pop a pill to stave off ‘senior moments’.

However, exactly such a pill could be on the cards, thanks to work underway at the Center for Addiction and Mental Health in Toronto. The researchers, led by Dr Etienne Sibille, are developing a new type of therapy that could reverse everyday memory lapses.

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.

Sibille’s molecules do hold potential for Alzheimer’s disease. However, they 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.

“Cognitive deficits have not been considered an endpoint for drug development in psychiatric disorders until recently, hence little effort was devoted to it,” says Sibille, who is deputy director of the Campbell Family Mental Health Research Institute at CAMH. “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.”

How the drug works

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 like Alzheimer’s, and normal ageing.

“These novel molecules increase the function of a specific type of inhibitory GABAergic interneurons, which are deficient in many brain disorders,” explains Sibille.

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.

Reporting their findings in Molecular Neuropsychiatry in January, Sibille’s team conducted a study on mice. They homed in on the impaired GABA receptors that are responsible for memory lapses. Then they tested out the new molecules, which are designed to fix these impairments.

So far we have shown that our novel compounds enter the brain and are safe.

In a series of experiments, mice received a single dose of the drug, and were placed in a maze. Some of these mice were old (and therefore had naturally poorer memories) whereas some were young but had been subjected to stress-induced memory loss. After half an hour, the young mice had seen their memories restored while the old mice performed nearly as well as the young ones.

In another experiment, old mice had the drug put in their drinking water, and saw improvements lasting over two months. In fact, their damaged brain cells, which had shrunk with age, were rejuvenated. This suggests the drug can renew the underlying brain impairments, as well as improving cognitive symptoms.

“So far we have shown that our novel compounds enter the brain and are safe. At the behavioural level they display pro-cognitive effects in stress and aged mouse models, in addition to reducing anxiety and potentially depression,” says Sibille.

Possible indications

Clearly, mouse models can only tell us so much, and it will be a while before these results are replicated in humans. However, the researchers have submitted a patent for the drug, and expect to begin phase I trials in 2021.

“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,” says Sibille.

After the safety trials, the researchers want to test the drug on adults with depression, and then on those with age-related cognitive decline. Ultimately they think that anyone over the age of 55-60, who may be at risk of cognitive problems later in life, could benefit from the treatment (ideally in the form of one pill a day). This could help prevent memory loss in early-stage Alzheimer’s, and even delay the onset of the condition.

The first indication we are thinking of is cognitive dysfunctions in adult depression.

“The first indication we are thinking of is cognitive dysfunctions in adult depression,” says Sibille. “The next indications would be cognitive deficits during ageing and neurodegenerative disorders. We will test our novel compounds in rodent models of Alzheimer’s in the next few months.”

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.

Another approach to tackling ageing-related cognitive dysfunction

Sibille presented his findings at the American Association for the Advancement of Science annual meeting in February. He was not the only speaker broaching the topic of cognitive decline.

Professor Daniela Kaufer at the University of California, Berkeley, and Professor Irina Esterlis of Yale University, presented separate findings on how depression accelerates ageing in the brain. This further emphasises the need for medication that can tackle cognitive symptoms.

Kaufer’s team, like Sibille’s, is looking to develop a pill for ageing-related cognitive dysfunction. In their case, they are exploring how a ‘leaky’ blood-brain barrier – common to older people and depressed people – can cause inflammation in the brain. Kaufer has discovered a chemical that prevents this inflammation in mouse brains, not only halting future cognitive decline but reversing its underlying cause.

The next step is to ask questions of what this means for humans.

“This understanding from the mice is very exciting for us. The next step is to ask questions of what this means for humans,” she said at the meeting.

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.

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