Our systematic review and meta-analysis of neuroprotection in animal models of Stroke has already started to pay dividends, revealing many of the key determinants of success in the thread occlusion model of Stroke, which classes of neuroprotectants are truly effective in animals and the magnitude of their effect, some uncomfortable truths about the conduct of much animal experimentation and the fact that very often we have not taken the most effective animal drugs on to human trial. We shall continue this approach with three specific aims, first to understand the value of specific classes of drugs and second to determine whether combinatorial therapy offers any advantage over single drug therapy. The third aim will be to accumulate sufficient data (we have collected data from 8,500 of the planned 10,000 animals) and to fully evaluate the importance of animal strain, age, co-morbidities, physiological variables and experimental design in the study of stroke.
We are also taking an experimental approach to improving the rodent models of stroke. By re-design of the threads used to occlude the middle cerebral artery we have improved the model to allow its successful used in aged diabetic and hypertensive rats while improving success rates and considerably reducing mortality.
We will also determine the mechanism behind our observation of neuroprotection by ACE inhibition is independent of blood pressure and test our hypothesis that neuroprotection may be pointless unless axons and dendrites are also protected or prompted to regenerate. It is surprising how little is know about the extent or distribution of axonal and dendritic injury after stroke or about whether these anatomical structures which define the connectivity and function of the brain are protected in any way by neuroprotective drugs.
Finally, a fundamental construct in our understanding of stoke and our attempts at neuroprotection is the concept of an “ischaemic penumbre”, which sustains damage but is not killed out-right. Since it is this “penumbra” which we seek to protect it is important that we can identify it and understand it’s biology. To this end, in collaboration with the PET Centre at Austin Health and Professor Donnan’s clinical team, we are examining the utility of novel nitroimidazole compounds to bind irreversibly to sub-critically damaged tissue. We have shown that one such compound, FMISO, can be used to delineate the penumbra after stroke and are currently determining its cellular and sub-cellular binding pattern.
The following projects are investigated by the Howells group:
Neuroprotection after stroke
If nerve cells in the brain can be protected from damage after stroke, then the damage caused will be reduced. Having performed an extensive review of neuroprotection after stroke in animal models, we have determined the most effective therapies in animal models and plan to test these in human trials. We are also testing new compounds for their neuroprotective effect in animals.
Researchers currently working on project:
Assoc Prof David Howells, Ms Susan Cox, Ms Victoria O’Collins, Dr Michelle Porritt, Ms Sarah Rewell, Ms Elena Aleksoska
Axonal injury and recovery after stroke
While many projects have studied damage to nerve cell bodies after stroke, few have studied the damage caused to connections between nerve cells (axons). We are studying how axons are injured and if they regenerate after a stroke and whether new connections between nerve cells are made.
Researchers currently working on project:
Assoc Prof David Howells, Dr Michelle Porritt, Dr Peter Batchelor, Ms Elena Aleksoska, Ms Susan Cox, Ms Sarah Rewell
Development of seizures after ischemic stroke
This project aims to understand the mechanisms which underlie the development of epilepsy after a stroke. Video-EEG is being used to determine the time of onset, frequency and nature of seizures after animal stroke. Gene expression studies comparing animals that do or don’t have seizures will start the process of identifying the causes of a predisposition to seizures.
Researchers currently working on project:
Assoc Prof David Howells, Assoc Prof Terence O’Brien (Dept of Medicine, Royal Melbourne Hospital), Dr Michelle Porritt
National Stroke Research Institute
