Cambridge scientists have developed and tested a new drug in mice that has the potential to reduce damage to the brain when blood flow is restored following a stroke.<\/p>\n
As many as one in four people will have a stroke during their lifetime. This is when a blood clot prevents oxygen from reaching a part of the brain. The first few hours following a stroke are crucial \u2013 the blood clot needs to be removed quickly so that the oxygen supply to the brain can be restored; otherwise, the brain tissue begins to die.<\/p>\n
Currently, the outcome for stroke patients receiving even the best available treatment, known as mechanical thrombectomy, is still poor, with fewer than one in 10 patients leaving hospital with no neurological impairment.<\/p>\n
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Stroke is a devastating disease. Even for those who survive, there is a significant risk of damage to the brain that can lead to disabilities and a huge impact on an individual’s life. But in terms of treatment, once the stroke is happening, we have only limited options.”<\/p>\n
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Professor Thomas Krieg, Department of Medicine, University of Cambridge\u00a0<\/p>\n
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Mechanical thrombectomy is a\u00a0minimally invasive medical procedure involving the insertion of a\u00a0thin tube, known as a catheter,\u00a0into a blood vessel, often through the groin or arm. This is guided to the blood clot,\u00a0where it is removed by a\u00a0tiny device, restoring normal blood flow.<\/p>\n
Restoring blood flow too suddenly\u00a0can make things worse, however. This is called\u00a0ischaemia-reperfusion injury. When blood rushes back into the oxygen-starved tissue (a process known as reperfusion), the damaged cells struggle to cope, leading to the production of\u00a0harmful molecules\u00a0called\u00a0free radicals\u00a0that can\u00a0damage cells, proteins, and DNA. This triggers further damage and can cause an inflammatory response.<\/p>\n
The Cambridge team has previously shown that when the brain is starved of oxygen, a build-up occurs of a chemical called succinate. When blood flow is restored, the succinate is rapidly oxidised to drive free radical production within mitochondria, the ‘batteries’ that power our cells, initiating the extra damage. This occurs within the first few minutes of reperfusion, but the researchers showed that the oxidation of succinate can be blocked by the molecule malonate.<\/p>\n
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All of this happens very rapidly, but if we can get malonate in quickly at the start of reperfusion, we can prevent this oxidation and burst of free radicals.<\/p>\n
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We discovered in our labs that we can get malonate into cells very quickly by lowering the pH a little, making it a bit more acidic, so that it can cross the blood-brain barrier better. If we inject it into the brain just as we’re ready to reperfuse, then we can potentially prevent further damage.”<\/p>\n
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Professor Mike Murphy from the Medical Research Council Mitochondrial Biology Unit<\/p>\n
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In a study published in Cardiovascular Research, the team has shown that treating the brain with a form of the chemical known as acidified disodium malonate (aDSM) alongside mechanical thrombectomy greatly decreased the amount of brain damage that occurs from ischaemia-reperfusion injury by as much as 60%.<\/p>\n
Dr Jordan Lee, a postdoctoral researcher in the group, developed a mouse model that mimics mechanical thrombectomy, allowing the team to test the effectiveness of aDSM against ischaemia-reperfusion injury.<\/p>\n
Dr Lee said: “This approach reduces the amount of dead brain tissue resulting from a stroke. This is incredibly important because the amount of dead brain tissue is directly correlated to the patient’s recovery \u2013 to their disability, whether they can still use all their limbs, speak and understand language, for example.”<\/p>\n
Mechanical thrombectomy is increasingly used in the NHS, and the researchers hope that with the addition of aDSM as a treatment alongside this intervention, they will be able to improve outcomes significantly when the procedure is more widely adopted.<\/p>\n
The team has launched Camoxis Therapeutics, a spin-out company, with support from Cambridge Enterprise, the innovation arm of the University of Cambridge. It is now seeking seed funding to develop the drug further and take it to early-stage clinical trials.<\/p>\n
Professor Murphy added: “If it’s successful, this same drug could have much wider applications for other instances of ischemia-reperfusion injuries, such as heart attack, resuscitation, organ transplantation, and so on, which have similar underlying mechanisms.”<\/p>\n
The research was supported by the British Heart Foundation, Medical Research Council, Wellcome Trust and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.<\/p>\n
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