Chilling the body with drugs could limit brain damage from stroke

A combination of two drugs used to treat hay fever and psychosis cooled down the core body temperature of mice and monkeys, reducing brain damage after a stroke. These medications have also undergone preliminary testing in people, and will now be evaluated in a follow-up clinical trial.

Researchers have spent decades investigating ways to chill people’s brains after they have a stroke to try to limit the damage. The idea is to freeze brain cells in a hibernation-like state so they don’t need as much oxygen and glucose when a stroke cuts off their blood supply. If brain cells can be kept alive until blood flow is restored, for example, by removing a clot, a patient may be spared from extensive brain damage and related speech and movement problems.

Unfortunately, the physical cooling strategies that have been looked at so far – including cooling blankets, ice packs and helmets – haven’t worked well. This is because they cause intense discomfort and uncontrollable shivering, says Kirsten Coupland at the University of Newcastle in Australia, who wasn’t involved in the study.

Shivering is one method the body uses to “fight the induction of hypothermia”, making it hard to get body temperature down low enough, she says. “It’s great to see different cooling therapies being tested out for stroke because we know that physical cooling is just not feasible,” says Coupland.

Shuaili Xu at Capital Medical University in Beijing, China, and his colleagues administered the two drugs, promethazine and chlorpromazine, which have been known to reduce body temperature since the 1950s, to mice and rhesus monkeys following induced strokes.

In both animals, the drug combination led to drops in core body temperature, suppressed glucose metabolism in cells and lessened the amount of brain damage caused by the stroke. The reduced brain damage also meant the treated monkeys displayed better use of their limbs.

Next, the team conducted a clinical trial involving 32 people who had just had a stroke. Upon hospital admission, the subjects were given the promethazine and chlorpromazine combination or a placebo, in addition to standard clot-removal therapy.

The promethazine and chlorpromazine treatment only reduced the patients’ body temperature by 0.3°C (about 0.5°F) and did not reduce stroke damage. However, Xu thinks this is because the infusions were done over 12 hours, which was too slow to bring down core body temperature by a meaningful amount. “It might have led to a low blood drug concentration per unit of time,” he says.

His team is now launching another trial to see whether faster infusions over an hour produce stronger cooling effects and therapeutic benefits. “The fact that they’ve proven that it’s safe and these drugs are already used in humans for other indications means I think that it’s reasonable to proceed with further clinical trials,” says Coupland.

Promethazine and chlorpromazine are known to be relatively safe because they have been used for decades. Promethazine is a sedating antihistamine that can ease hay fever and assist sleep, while chlorpromazine is an antipsychotic drug used in the management of schizophrenia and bipolar disorder. They both act on the central nervous system to reduce core body temperature, without translating into shivering or subjective feelings of coldness.