The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery

Dopamine, a major neurotransmitter, plays a role in a wide range of brain sensorimotor functions. Parkinson's disease and schizophrenia are two major human neuropsychiatric disorders typically associated with dysfunctional dopamine activity levels, which can be alleviated through the druggability of the dopaminergic systems. Meanwhile, several studies suggest that optimal brain dopamine activity levels are also significantly impacted in other serious neurological conditions, notably stroke, but this has yet to be fully appreciated at both basic and clinical research levels. This is of utmost importance as there is a need for better treatments to improve recovery from stroke. Here, we discuss the state of knowledge regarding the modulation of dopaminergic systems following stroke, and the use of dopamine boosting therapies in animal stroke models to improve stroke recovery. Indeed, studies in animals and humans show stroke leads to changes in dopamine functioning. Moreover, evidence from animal stroke models suggests stimulation of dopamine receptors may be a promising therapeutic approach for enhancing motor recovery from stroke. With respect to the latter, we discuss the evidence for several possible receptor-linked mechanisms by which improved motor recovery may be mediated. One avenue of particular promise is the subtype-selective stimulation of dopamine receptors in conjunction with physical therapy. However, results from clinical trials so far have been more mixed due to a number of potential reasons including, targeting of the wrong patient populations and use of drugs which modulate a wide array of receptors. Notwithstanding these issues, it is hoped that future research endeavors will assist in the development of more refined dopaminergic therapeutic approaches to enhance stroke recovery

Heme Oxygenase 1 expression after traumatic brain injury and effect of pharmacological manipulation on functional recovery.

Traumatic Brain Injury (TBI) is an increasingly diagnosed constellation of injuries derived from acute mechanical trauma to the brain. With the rise of advanced neuroimaging techniques recent focus has oriented primarily towards the mild-moderate range of TBI which previously was missed diagnostically. Characteristically, these advances have shown increasing areas of micro-hemorrhage in susceptible areas of the brain and to date there are no treatment modalities targeting micro-hemorrhages or their sequelae. This dissertation explores the effects of the resulting heme processing response in the days following injury with a particular focus on inducing early heme clearance from the parenchyma using a rat central fluid percussion injury model in the mild-moderate injury range. Since heme is released ~24-48 hours post-injury and is known to be cytotoxic we observed there may be a critical window for treatment to clear heme before it is spontaneously released and to increase the buffering capacity of the tissue. We targeted heme clearance by using drugs known to increased expression of Nrf2, an upstream transcriptional regulator of the canonical heme processing protein heme oxygenase 1 (HO-1), and tracking expression of HO-1, the iron sequestration/storage proteins Lipocalin 2 (LCN2) and Ferritin (FTL), as well as the activity of matrix metalloproteinases 2 and 9 (MMP2, MMP9). We examined both tissue known to be frankly hemorrhagic (the neocortex) as well as tissue lacking any identifiable bleed (the hippocampus). We demonstrated that using the HO-1 inducers Hemin and Sulforaphane in a single dose paradigm given 1 hour post-injury heme clearance was accelerated in the neocortex with the majority of heme pigment processed by 24 hours post-injury. Further there was significant attenuation of protein expression in HO-1 and ferritin as well as the enzyme activity of MMP2 and MMP9 in both the neocortex and the hippocampus. Behavioral attenuation was also seen in both rotarod and Morris water maze tests. While we intended to target hemorrhagic processing after injury, and indeed demonstrated improved clearance of heme from post-injury hemorrhagic regions of the brain, in both tissues studied we observed remarkably similar responses to the drugs utilized in protein expression, enzyme activity, and behavioral improvement which may suggest a globally improved pathologic state or that there are unidentified pathologic micro-hemorrhages or leaky vessels which extend further into the brain parenchyma than currently identified

Mobilisation of endogenous haematopoietic stem cells and their use as treatment for subacute stroke

The potential application for stem cell therapy is vast. Despite a limited understanding of their mechanisms of action, clinical trials assessing stem cells in human stroke are underway. Colony stimulating factors (CSF) such as granulocyte colony stimulating factor (G-CSF), which have been used to mobilise haematopoietic stem cells (HSC), also show promise in treating stroke. Preclinical experiments evaluating the effect of G-CSF in stroke were meta-analysed; G-CSF significantly reduced lesion size in transient but not permanent models of ischaemic stroke. Further studies assessing dose-response, administration time, length of ischaemia and long-term functional recovery are needed. Tracking iron-labelled cells with MRI may help to establish migratory patterns following transplantation. Our systematic review of iron-labelled stem cells in experimental stroke suggests that compounds already licensed for humans (ferumoxide and protamine) may potentially be used in clinical trials. In a phase IIb single-centre randomised controlled trial (n=60), the safety of G-CSF in recent stroke was assessed (STEMS-2). G-CSF appears safe when administered subacutely and may reduce stroke lesion volume. Phase III trials are required to test efficacy. An updated Cochrane review on CSFs in stroke shows that G-CSF was associated with a non-significant reduction in early impairment but had no effect on functional outcome in 6 small studies. In two trials, erythropoietin therapy was significantly associated with death by the end of the trial. It is too early to know whether G-CSF could improve functional outcome in stroke. In 8 recruits randomised into STEMS-2, mobilised CD34+ HSCs were paramagnetically labelled, re-infused and tracked with serial T2* MRI. Post-stroke HSC labelling appears safe and feasible. There is suggestive evidence in one patient that labelled HSCs migrate to the ischaemic lesion. Our in vitro evaluation of CD34+ HSCs has revealed that uptake of superparamagnetic iron oxide (SPIO) is enhanced but not dependent upon a transfection agent. Iron labelling of CD34+ cells in this manner did not affect cell viability or inhibit growth. This methodology could be applied to clinical trials. We have established the expression of G-CSF protein, its receptor (G-CSFR) and CD34 antigen in post-mortem brain tissue from participants recruited to STEMS-2. Areas of angiogenesis and expression of G-CSFR in acute and chronic infarction suggest potential targets for therapy. There are many preclinical studies reporting the effects of stem cells in treating stroke (with a noticeable lack of neutral or negative articles). Despite the wealth of literature there remain many unanswered questions and patients should not undergo stem cell therapy unless it is as part of a well designed clinical trial

Advances in the Treatment of Ischemic Stroke

In recent years research on ischemic stroke has developed powerful therapeutic tools. The novel frontiers of stem cells therapy and of hypothermia have been explored, and novel brain repair mechanisms have been discovered. Limits to intravenous thrombolysis have been advanced and powerful endovascular tools have been put at the clinicians' disposal. Surgical decompression in malignant stroke has significantly improved the prognosis of this often fatal condition. This book includes contributions from scientists active in this innovative research. Stroke physicians, students, nurses and technicians will hopefully use it as a tool of continuing medical education to update their knowledge in this rapidly changing field

Mobilisation of endogenous haematopoietic stem cells and their use as treatment for subacute stroke

The potential application for stem cell therapy is vast. Despite a limited understanding of their mechanisms of action, clinical trials assessing stem cells in human stroke are underway. Colony stimulating factors (CSF) such as granulocyte colony stimulating factor (G-CSF), which have been used to mobilise haematopoietic stem cells (HSC), also show promise in treating stroke. Preclinical experiments evaluating the effect of G-CSF in stroke were meta-analysed; G-CSF significantly reduced lesion size in transient but not permanent models of ischaemic stroke. Further studies assessing dose-response, administration time, length of ischaemia and long-term functional recovery are needed. Tracking iron-labelled cells with MRI may help to establish migratory patterns following transplantation. Our systematic review of iron-labelled stem cells in experimental stroke suggests that compounds already licensed for humans (ferumoxide and protamine) may potentially be used in clinical trials. In a phase IIb single-centre randomised controlled trial (n=60), the safety of G-CSF in recent stroke was assessed (STEMS-2). G-CSF appears safe when administered subacutely and may reduce stroke lesion volume. Phase III trials are required to test efficacy. An updated Cochrane review on CSFs in stroke shows that G-CSF was associated with a non-significant reduction in early impairment but had no effect on functional outcome in 6 small studies. In two trials, erythropoietin therapy was significantly associated with death by the end of the trial. It is too early to know whether G-CSF could improve functional outcome in stroke. In 8 recruits randomised into STEMS-2, mobilised CD34+ HSCs were paramagnetically labelled, re-infused and tracked with serial T2* MRI. Post-stroke HSC labelling appears safe and feasible. There is suggestive evidence in one patient that labelled HSCs migrate to the ischaemic lesion. Our in vitro evaluation of CD34+ HSCs has revealed that uptake of superparamagnetic iron oxide (SPIO) is enhanced but not dependent upon a transfection agent. Iron labelling of CD34+ cells in this manner did not affect cell viability or inhibit growth. This methodology could be applied to clinical trials. We have established the expression of G-CSF protein, its receptor (G-CSFR) and CD34 antigen in post-mortem brain tissue from participants recruited to STEMS-2. Areas of angiogenesis and expression of G-CSFR in acute and chronic infarction suggest potential targets for therapy. There are many preclinical studies reporting the effects of stem cells in treating stroke (with a noticeable lack of neutral or negative articles). Despite the wealth of literature there remain many unanswered questions and patients should not undergo stem cell therapy unless it is as part of a well designed clinical trial