Drugs that treat diseases of the brain are notoriously difficult to create. The first barrier to the development of these drugs is physical—the blood-brain barrier (BBB) acts as a bouncer for the brain, filtering all blood flowing in. The second barrier is biological. Even if a drug is able to sneak its way past the BBB sentries, there is no guarantee that the drug will have its intended effect. The brain is intimately connected, so any molecule that attempts to modify one system for a therapy will have unintended consequences on the other brain systems. For these two reasons, drugs that treat conditions like cognitive decline and depression are few and far between.
Enter Etienne Sibille, deputy director and senior scientist at the Campbell Family Mental Health Research Institute and professor at the Univeristy of Toronto. Sibille and his team have spent the past ten years researching potential therapies to treat depression and cognitive decline. Their recent work has finally uncovered a class of molecules—imidazobenzodiazepine (IBZD) amides—that appear to treat both of these conditions in adult mouse models. Further research and clinical trials will determine the efficacy of these drugs on humans, but if the results hold, Sibille and his team’s work will have a lasting impact on the way these neurological diseases are treated.
GABA: the brain’s brake
The first step in Sibille’s ten-year-long journey was to understand what exactly was different in the brains of people with depression and cognitive deficits. “The idea for my group was to do broad searches for molecular changes in the context of depression and aging,” Sibille said. Sibille and his team spent years analyzing different systems of the brain, and they eventually zeroed in on signaling by gamma-aminobutyric acid (GABA).
Your brain transmits, stores, and produces information through the signaling of roughly ninety billion neurons, specialized cells designed by nature for this purpose. Each neuron is composed of dendrites, the soma (or cell body), and an axon. They receive signals through their dendrites in the form of chemical signals or electricity, transmit those signals through the soma, and finally, if the signal is strong enough, pass along their message through the axon and into the waiting arms of another neuron’s dendrites. Just like a binary bit on a computer, which can be either a one or a zero, a neuron can either be on or off. For computers, the combination of billions of bits makes a MacBook Pro possible. For brains, the summation of these on/off signals over billions of neurons create complex systems that lead to memory formation, sensory reception, and executive function.
GABA is one of many molecules—termed neurotransmitters—that do the actual signaling between the axons and dendrites of neurons. It is released primarily by GABA interneurons—a specific subset of neurons—and functions as the major inhibitory neurotransmitter in every animal brain. If transported by the axon of one neuron to the dendrite of another neuron, GABA will effectively turn off the receiving neuron and prevent any further signaling. This axon to dendrite interaction is mediated by different types of GABA receptors on the receiving dendrite. GABA’s inhibitory function is crucial to any type of nervous system, and thus, GABA has been conserved over hundreds of millions of years of evolution. In fact, GABA signaling is even seen in certain species of sponges, the oldest and simplest evolutionary example of a nervous system.
As such a crucial neurotransmitter, altered GABA function is implicated in a wide range of neurological diseases, including depression, anxiety, and even Alzheimer’s. Depression has previously been linked to a GABA deficiency, and a recently approved treatment for postpartum depression appears to work by inducing changes in the GABA system. Recent work has even linked GABA dysfunction to age-related memory deficits. Consequently, Sibille and his team focused their initial work on this system and found significant functional reduction in the SST+ interneuron—a type of GABA neuron—in the brains of those with cognitive deficits and depression.
Alpha-5 receptors: a specific target
To some extent, all therapeutic drugs are at least slightly toxic to the body. The key to any drug is how much of it can be tolerated before debilitating symptoms start to occur. In many cases, the toxicity of a drug is related to its specificity—the ability of a drug to interact only with the target of interest. Undesirable interactions are often what cause these side effects.
Many drugs that treat depression and cognition have suffered from this issue—they simply aren’t specific enough to be a viable treatment. Benzodiazepines (BZs) are prescribed to alleviate anxiety and depression, but they have effects on a broad swath of GABA receptors and thus have serious side effects on patients, including sedation, hypnosis, and difficulties with movement.
Sibille and his team’s pinpointing of SST+ interneurons allowed for them to target one specific GABA receptor. These interneurons largely signal dendrites with α5-GABAA receptors, which means that drugs that target just this receptor type can be specific and thus have limited side effects. The researchers spent the past four years synthesizing and testing various molecules for this purpose. After a few unsuccessful attempts, they found that certain IBZD amides appear to be both specific and effective in treating depression and cognitive decline.
This study tested four IBZD amide variants for their potential as therapeutic drugs, using adult mice as a model. The researchers first looked at the ability of the IBZD amide variants to pass the BBB and enter the brain, as the drugs can only work if they reach their destination. Three of the four molecules were found to have adequate brain penetration and were studied further.
From there, the molecular effects of each IBZD amide was characterized. All three were found to target and activate α5-GABAA receptors with the greatest priority, but all three also had slight activation of the more broadly expressed α1-GABAA receptors.
Next, the ability of these drugs to treat depression and cognitive dysfunction were measured. Although depression is hard to characterize in mice, Sibille and his team observed the mice for locomotive traits such as mobility and willingness to go into open arms as predictors of antidepressant effects. Two of the IBZD amides were found to increase the prevalence of these traits. For cognitive deficits, the researchers tested the ability of these molecules to restore normal short-term memory that declined as a result of stress or old age. The same two molecules that suppressed depressive symptoms were also found to significantly reduce the negative impact of stress and old age on working memory deficits.
Interestingly, the extraneous activation of α1-GABAA receptors may be the reason why these molecules are able to improve the cognition of mice. Sibille and his team previously tested molecules that solely and strongly target α5-GABAA receptors, but they were found to have no effects on cognition. Sibille theorizes that slight activation of α1-GABAA receptors is somehow also necessary for functional working memory, meaning that the slight non-specific effects of these drugs actually contributes to their function.
The future of the therapy
The next step for Sibille and his team is to understand fully what side effects these molecules may have. Before they can proceed to human clinical trials, Sibille said they are required by the FDA to test potential interactions of these drugs with other substances—such as alcohol—and with other brain systems, such as the addictive reward system. Sibille said that IBZD-like molecules are often hailed for their lack of side effects and that more than twenty studies testing similar molecules found no adverse effects.
There are currently no drugs on the market that treat cognitive deficits, and the select few that treat depression are not well understood and only work some of the time. Sibille is particularly excited about the potential of these drugs to treat cognitive defects. “The novelty [of this research] is that there is really nothing for cognition,” he said. “If the cognition results hold true in humans, that is a big deal.” If clinical trials succeed, one can imagine doctors using IBZD amides to treat everything from age-related memory loss to the early stages of Alzheimer’s. Drugs that treat neurological disorders may be difficult to create, but the decade of work Sibille and his team have put into drug development appear to have paid off.