/ 18 August 2014

The sleeping pill that wakes up damaged brains

Top-down molecular model of the cellular receptor
Top-down molecular model of the cellular receptor

A conservative estimate, based on hospital records from the 1990s, estimates that 170 000 people sustain brain damage every year. Sadly there is little than can be done to treat an injured brain, with the majority of post-accident interventions focussing on preventing further damage. Many of these patients end up in rehabilitative or palliative care for the rest of their lives. This is where our research on Zolpidem comes in.

As a researcher, I remember the first time that I was introduced to a group of Zolpidem responder patients. It’s not quite the elegant tale of the confident young neuroscientist swooping in with a charming smile and excellent bedside manner to have rousing conversations with enthusiastic patients who had been completely restored by a wonder drug. 

Instead, I stood frozen in the doorway of a small preparation ward, caught completely off guard by the three families in front of me as a nurse armed with syringes encased in lead shields moved between vulnerable patients with militant precision. She was administering a radioactive tracer in preparation for a SPECT scan, a unique way of imaging brain function by measuring blood flow.

The three patients, each with varying forms of brain damage, were lying on hospital beds. One was asleep. The other two were suffering incapacitating muscle spasms as their significant others sat next to their beds gingerly trying to do whatever they could to comfort their loved ones. 

I was acutely aware of the immense importance of this research and any associated discoveries, as even the smallest improvements can have a large impact on these bed-ridden patients’ quality of life.

Selling at just over R7 per 10mg tablet, Zolpidem, originally marketed as Stilnox in South Africa, was developed by the French pharmaceutical corporation Sanofi-Aventis as a sleeping pill. In healthy individuals, it decreases the amount of time required to fall asleep (known as sleep latency). But if you give this pill to someone with brain damage, in 5% to 6% of cases something miraculous happens. Often it’s a small change, an improvement in speech, reduced muscle spasms, improved gait. In drastic cases, patients are roused from vegetative states, returning to consciousness after many months, even years, of being completely unresponsive. It is these unbelievable events that have led to Zolpidem being dubbed by some as a “Lazarus Drug”.

The problem is, no one knows exactly how it is able to restore function to damaged brains. Bizarrely, once the drug wears off, so do the beneficial effects and vegetative patients are once again subconscious. If the dose is too high, the beneficial effects give way to the drug’s action as a sleeping pill.

So far researchers have been unable to pinpoint which patients will respond positively to the drug. There does not seem to be a particular type of brain damage or damage to a particular region of the brain that dictates, with certainty, whether there will be a rehabilitative response to Zolpidem. But that has not stopped researchers from hypothesising. 

One of the first theories was put forward by a research team from the Medical University of Southern Africa working in conjunction with the Royal Surrey County Hospital (UK): the pioneering concept of “neurodormancy”.

Established physiology states that after a traumatic brain injury, lightly damaged brain cells (neurons) will fully recover, whereas profoundly compromised cells will die off, often taking their neighbours with them. The neurodormancy hypothesis proposes a third option: select populations of neurons are caught in a grey zone between death and recovery. These cells are able to hibernate, buying themselves the necessary time to repair. However, occasionally, something goes wrong: instead of completing their repairs and waking up, they remain dormant.

Zolpidem works by binding to a specific cellular target, known as GABA receptors, and enhances the effect of gamma-aminobutyric acid (GABA), a signalling molecule. When it binds to these receptors, Zolpidem turns off individual brain cells. When you’re falling asleep, it is the release of GABA that steadily reduces the activity of brain cells. The neurodormancy hypothesis assumes that these hibernating cells have become supersensitive to GABA, and this is why they remain turned off. These scientists argue that Zolpidem transiently restores normal levels of GABA sensitivity, rousing the dormant cells.

A research team at Cornell University (USA) has offered an alternate hypothesis linking Zolpidem and the interaction between brain regions. In the centre of your brain, sitting on top of the brainstem is a structure known as the thalamus. It acts as a vital switchboard for information moving in, out and around your brain. Autopsies conducted on patients who died while they were in vegetative states found that a large percentage of them had damage to the thalamus or interconnected structures.

When operating as expected, there is a region of the brain (the globus pallidus interna), which is constantly trying to turn the thalamus off. Crucially, this region is itself shut down by a separate centre, the striatum. If the striatum detects enough background activity, it turns the globus pallidus off, leaving the thalamus to perform its duties unimpeded, and we perceive this as being conscious.

The problem arises in patients in comas and vegetative states where, either through damage to the network or to itself, the striatum no longer detects enough background activity to facilitate the shutdown of the globus pallidus interna. This allows the globus pallidus interna to run the show and turn the thalamus off — and this is also where Zolpidem comes in. Through silencing the globus pallidus interna, it eliminates the “off” impulse being sent to the thalamus, effectively flipping the thalamic’s “on” switch, reactivating the central switchboard and restoring consciousness.

Sadly neither of these hypotheses is perfect, or able to explain the complex spectrum of Zolpidem-related phenomena. However, researchers are still trying to take full advantage of Zolpidem’s unique action as well as developing new drugs which work in a similar manner. Despite the theoretical uncertainties, Zolpidem offers a glimmer of hope for many families coping with the aftermath of a loved one’s brain injury.

Petrie Jansen van Vuuren is a MSc candidate at the University of Pretoria