Antoine M. Hakim, O.C., MD, PhD, FRCPC Telephone: 613-562-5462 Fax: 613-562-5403 Roger Guindon Hall (see Contact page for maps)

Director, Neuroscience, Ottawa Hospital Research Institute

Senior Scientist, Neuroscience, Ottawa Hospital Research Institute

• bringing together Canada's stakeholders in stroke and helping them gain access to the resources they need to excel;
  
• building a national network that supports collaborative research, and
  
• promoting the interests of science with the goal of improving health and the quality of life of stroke survivors.
  

My laboratory-based research activities were frequently guided by my clinical exposure to patients with neurological problems. During my neurology residency I was intrigued with Wernicke-Korsakoff patients who exhibit severe memory deficits in association with alcoholism and thiamine deficiency but show only very limited brain lesions. I began to study how systemic conditions result in focal brain damage. This led to an interest in stroke because of the selective nature of the damage caused by ischemic deprivation. Specifically, my fundamental research activities have included:

a) Investigation of the biochemical, ionic, molecular and receptor events that determine cerebral vulnerability in metabolic deficiencies and in stroke.
My laboratory described the focal cerebral events that precede the appearance of pathological damage during prolonged deficiency of thiamine and B12. In these settings, and subsequently in focal ischemia, we correlated in time and space the glucose utilization and acidosis that precede the focal appearance of histologically evident damage, and showed how reversing the metabolic or vascular deficiency resulted in a specific sequence of reversal of these metabolic abnormalities, e.g. the appearance of alkalosis. The simultaneous measurement of pH and glucose utilization or blood flow was made possible by an innovation to autoradiography we developed involving sublimation of the pH marker after we had measured its radioactivity in brain.
Subsequently, I focused on cerebral ischemia and correlated hyperglycemia with the severity of focal acidosis in that setting. The association of hyperglycemia with worsened outcome in stroke was subsequently shown in stroke patients. Concepts derived from our animal studies guided studies we performed in stroke patients in the acute phase, using Positron Emission Tomography (PET). We correlated in these patients the anatomic-metabolic-functional parameters with focal cerebral blood flow changes and radiological/clinical outcomes. These studies allowed us to describe the ischemic penumbra in patients and show its progression in time and space. We went back to the animals and showed that cells in the penumbra region die by apoptosis while those in the ischemic core die by necrosis, and verified that as the ischemia becomes more prolonged necrosis sweeps over regions of apoptosis. This led us to investigate the molecular determinants of apoptotic cell death, and we showed that cyclin-dependent kinases trigger apoptosis and that inhibiting them leads to neuroprotection. We also reported that activating neuronal-apoptosis-inhibitory-protein (NAIP) provides neuroprotection in the setting of apoptotic cell death.

My laboratory also reported the dependence of calcium channel activity on focal blood flow changes, and in an ischemia-reperfusion model, showed the reversibility of calcium channel activation with associated tissue survival. In the stroke patients, we used PET to study the effect of administering nimodipine on metabolic function. Because clinical trials were contemplated with nimodipine, we studied and reported the kinetics of binding of nimodipine in vivo, which allowed us to suggest in various forums the enormous challenge this agent would face as a therapeutic modality.

b) Determination of conditions for neuroprotection against ischemic damage.
We first studied the relevance of interstitial glutamate levels on selective vulnerability in ischemia by correlating glutamate levels with activity of the calcium channels and histological outcome. This led us to investigate the concept of preconditioning, whereby short-duration ischemia, cortical depolarization, exposure to excitatory amino-acids or activation of calcium channels can improve the brain's resistance to subsequent ischemic damage. First, we described how short term global ischemia protects against subsequent focal ischemic damage, and then more thoroughly studied cortical spreading depression (CSD) as a laboratory tool to explain the preconditioning phenomenon and potentially use it therapeutically. We showed that CSD activated neurotrophic factors, decreased intra-ischemic glutamate levels, and down-regulated the transporters of the excitatory amino acids. More recently, we showed a number of molecular correlates of CSD, including a recent submission describing the changes in inflammatory cytokine protein levels in brain and plasma following CSD. My research colleagues and I are currently directing our attention to the modulation of a limited number of factors thought to play a role in the neuroprotective cascade.
c) Investigation of post-stroke plasticity and means of enhancing it.
My laboratory showed the regulation of nestin expression in focal brain injury. This is one of several developmental proteins activated in focal ischemia. Our special attention to this protein arose from our correlation of its activation with the mobilization of stem cells following focal ischemia, confirming that nestin is an essential protein in stem cell guidance. We have also published on the effect of low-dose amphetamine in patients recovering from stroke. This work has implications for our understanding of recovery and therapy after stroke.

My clinical studies focused on understanding the cerebral vulnerability to ischemia. I used PET in stroke patients to distinguish brain regions where cells are committed to die from those where they are still alive but not functioning, and tested the effect of various therapies administered in the acute phase on brain metabolic and perfusion parameters and correlated these with clinical and radiologic outcomes. I also contributed to studies which confirmed that, in stroke associated with atrial fibrillation, Coumadin was the appropriate therapy to prevent stroke recurrence. More recently we reviewed the lessons learned from negative stroke trials in an article titled: "Toward Wisdom from Failure: Lessons Learned from Negative Stroke Treatment Trials and New Therapeutic Frontiers". In this article, we outlined the shortcomings shared by previous stroke trials and described the experiments needed to increase the likelihood of success in translational stroke studies, a theme subsequently confirmed by the STAIR group. More recently, using data from the Registry of the Canadian Stroke Network, we reported the effect of calcium channel blockers on the outcome from stroke and showed that they could be beneficial. We are currently studying, using the data set in the Registry, the influence of statins on vulnerability to bleeding in response to t-PA in stroke patients. Earlier this year, we submitted a proposal to our Institutional Review Board to evaluate the response of stroke patients to Granulocyte Colony Stimulating Factor, an agent which releases bone marrow stem cells into the circulation and which may accelerate recovery from stroke.

Note: This is not a complete list of publications. More publications may be available in The Ottawa Hospital Library database and Pubmed (search by last name and initials).