Neuropharmacology xxx (2010) 1e4

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Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Post-stroke pharmacological intervention: Promoting brain recovery from injury in the futureq
Frank C. Barone*
SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1213, Brooklyn, NY 11203, USA

a r t i c l e i n f o
Article history: Received 17 August 2010 Accepted 19 August 2010

1. Filling the gap in stroke intervention Many vascular approaches to ischemic stroke intervention and prevention include as their goal maintenance of normal circulation or the reversal of vascular occlusion. Thrombolytic agents/mechanical instruments (e.g., tissue plasminogen activator; tPA, urokinase and mechanical devices) and anti-platelet and anti-thrombotic agents can protect the brain primarily by hemodynamic mechanisms. The majority of clinical trials have evaluated these (Ginsberg, 2008). Intravenous administration of tPA (i.e., to achieve thrombolysis of the occluded cerebral vessel) within 3 h is the only approved pharmacological treatment for ischemic stroke (Elijovich and Chong, 2010; National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995). Beyond 3 h after stroke onset, tPA administration exhibits increased risk of hemorrhagic conversion in the infarcted brain, generally results in negative outcome, and is contraindicated for safety reasons. Even though efforts are being made to extend tPA use to 4.5 h post-stroke for certain eligible patients (Del Zoppo et al., 2009), only a limited number (<5%) of patients qualify for its safe use. Therefore, in addition to preventative therapies, it is imperative to develop additional treatment interventions for ischemic stroke. Additional treatments of interest include agents that can: A) extend the time for safe tPA thrombolysis, B) directly protect brain cells if administered soon after stroke (i.e., neuroprotective interventions-Neuroprotection) and/or C) can improve brain recovery from injury even if administered after brain injury has occurred (i.e., neurorestorative interventions that can improve lost neurological function-Neurorestoration). Approaches beyond stroke prevention (e.g., extending the use of tPA, protecting the brain once a stroke

q Commentary on Recently Accepted Manuscript Neuropharm-D-10-00193R1: By Iaci et al., entitled Glial Growth Factor 2 Promotes Functional Recovery with Treatment Initiated Up to 7 Days after Permanent Focal Ischemic Stroke. * Corresponding author. Tel.: 1 718 221 5745; fax: 1 718 270 3840. E-mail address: frank.barone@downstate.edu.
0028-3908/$ e see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2010.08.016

occurs, improving functional outcome after stroke injury has occurred) are the focus of research at many levels (Carmichael, 2008; Del Zoppo et al., 2009; Ginsberg, 2008; Legos and Barone, 2003; Lo et al., 2003; Zhang et al., 2009). Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular event(s) that result in irreversible ischemic brain cell injury. Decades of work have dened the multiple mechanisms and mediators of ischemic brain injury, which have become the biological targets for neuroprotection (Ginsberg, 2008; Lo et al., 2003). Certainly the many experimental studies in animal models of brain ischemia, and the ability of hypothermia to protect the brain via multiple mechanisms, provide proof that protection of the brain can be achieved. However, none of the agents aimed at these biological targets of neuroprotection have exhibited clinical efcacy to date (i.e., there is no neuroprotective drug approved for use in stroke). There have been many suggestions why clinical efcacy has not been achieved. The list of reasons/excuses made for the abundance of failed neuroprotection trials includes: A) incomplete pre-clinical proling prior to clinical testing (e.g., suboptimal drug biochemical, physicalechemical and/or pharmaco-dynamic/brain penetration proles; multiple brain cell types and ongoing cellular pathological processes involved requires more extensive understanding of these interactions and of drug action), B) the need to treat pre-clinical studies more like clinical trials, including a full understanding of efcacy in different stroke models, in order to generate more translatable data, C) the lack of clinical trial study design to provide intervention within a required 4e6 h post-stroke time period (i.e., the therapeutic time-window known to be required for neuroprotection), and D) the lack of data conrming protectable penumbra brain tissue (i.e., determining protectable brain in patients requires imaging) (Barone, 2009; Chavez et al., 2009; Dirnagl, 2006; Feuerstein et al., 2008; Fisher et al., 2007, 2009; Ginsberg, 2008; Savitz, 2007; Savitz and Fisher, 2007; STAIR, 1999). So far, early thrombolysis that can provide blood supply to the ischemic brain has been the only successful intervention for ischemic stroke. Why nonvascular neuroprotective interventions, as a class, have not been successful in clinical trials certainly is not completely understood. However, both the clinical results and the hypothesis imply that we need to further understand: A) drug actions (Feuerstein et al., 2008), B) the multiple cell types, including white matter, and the neurovascular interactions

Please cite this article in press as: Barone, F.C., Post-stroke pharmacological intervention: Promoting brain recovery from injury in the future, Neuropharmacology (2010), doi:10.1016/j.neuropharm.2010.08.016

F.C. Barone / Neuropharmacology xxx (2010) 1e4

involved (Barone, 2009; Del Zoppo, 2009; Nedergaard and Dirnagl, 2005), C) how to better align the pre-clinical and clinical data and experimental designs as a prelude to future trials (Chavez et al., 2009; STAIR, 1999; Savitz and Fisher, 2007; Fisher et al., 2009). 2. From neuroprotection to neurorestoration Given the difculties in neuroprotection intervention for stroke, as one might expect, research began to focus on facilitating the spontaneous recovery of function that occurs following stroke injury (Gutirrez et al., 2009; Carmichael, 2008; Di Filippo et al., 2008). Please see the special issue that covers the meeting in Kananaskis, Alberta, Canada entitled Neuronal Plasticity: The Key to Stroke Recovery, (Neuropharmacology, 39(5), 2000). Neurorestorative approaches following stroke injury were investigated when we were only just beginning to understand the capacity of the mammalian brain to regenerate (Alvarez-Buylla and Lois, 1995; Lois et al., 1996). The earliest work in this area was the demonstration that basic broblast growth factor (bFGF) was expressed following stroke (Finklestein et al., 1990) and that bFGF administration long after stroke injury had occurred produced brain recovery from neurological decits (Kawamata et al., 1997a, 1997b). In the adult, neurogenesis from neural stem/progenitor cells continues from the subgranular zone (i.e., neurons) of the hippocampus dentate gyrus and from the subventricular zone lining the lateral ventricles (i.e., neurons and glia) and from glial progenitor cells in both the gray and white matter of the forebrain (Goldman, 2007; Zhang et al., 2008). Neuroblasts migrate from these areas and differentiate to mature granule cells and olfactory bulb interneurons. Following injury such as stroke, cells generated in the subventricular zone migrate also into areas which are not normally neurogenic, e.g., striatum and cerebral cortex, with post-stroke neuroinammation having mixed effects on this process (Barone and Feuerstein, 1999; Das and Basu, 2008; Ekdahl et al., 2009; Erlandsson et al., 2010; Kazanis, 2009; Lichtenwalner and Parent, 2006). Spontaneous brain regeneration associated with endogenous neural stem cells alone is inefcient for clinical improvement following brain injury, but their role in brain recovery can be augmented by application of exogenous growth factors (Greenberg and Jin, 2006; Leker et al., 2009). The potential of some factors on acute protection and brain regenerative effects has been investigated (Jerndal et al., 2010). Work utilizing exogenous stem/progenitor cells from multiple sources for intervention is at early stages, but has generated a lot of exciting data by exploring their opportunities for the future. Exogenously administered stem/progenitor cells (i.e., cell-based interventions) can generate neuronal, glial and endothelial cells, promote neurogenesis and angiogenesis but primarily modify the injured brain to improve brain plasticity, including myelin repair, axonal growth and synaptic connections, that facilitate restoration of function (Burns et al., 2009; Peru et al., 2008; Savitz et al., 2004; Xiong et al., 2010; Zhang and Chopp, 2009; Xu et al., 2010). Efforts to coordinate translational work in cell therapy are ongoing (Chopp et al., 2009). 3. Glial growth factor 2 produces brain functional recovery from injury The paper by Iaci et al. in the present issue of Neuropharmacology is coauthored by scientists from two companies that focus primarily on neurorestoration following brain injury/neurodegeneration (e.g., one that specializes in animal models of neurorestoration and another that specializes in neurorestorative pharmacological interventions). Their work investigates the effects of acute (i.e., early) and delayed post-stroke administration of two

Neuregulin-1 gene products (i.e., the full-length splice variant of glial growth factor 2; GGF2 and the C-terminal EGF-like ErbBreceptor binding domain fragment) on functional outcome measured using standard tests of neurological decits produced by stroke in rats. Although neither protein reduced stroke-induced brain injury, they did improve the recovery from neurological decits, thus restoring more normal function. Especially noteworthy, GGF2 exhibited extraordinary neurorestorative effects when administration began even up to 7 days after stroke. I am not aware of any pharmacological intervention that has demonstrated functional improvement when administered this long after brain injury in rodents (i.e., although I will refer below to efcacious cellbased intervention that work even much later). Certainly, improved functional outcome for a pharmacological agent that can be administered long after stroke has very signicant implications for stroke intervention. What is required now is an understanding of the GGF2 restorative mechanisms. No indication of brain changes that can explain the restorative effects of this protein is provided in this paper. Does it get into the brain? Does it affect brain ErbB-receptor mediated cellular signaling? Which cells? Does it alleviate secondary complications, affect inammation or promote brain repair? Does it induce brain regeneration and/or plasticity or a combination of these processes? As the authors indicate in their paper, functional recovery can also be improved by a range of neurorehabilitative procedures, such as physical training or exposure to an enriched environment (Johansson, 2000). How does GGF2 affect these and/ or additional cell-based intervention approaches? The fact that rehabilitative therapeutic efcacy declines with time post-stroke (Biernaskie et al., 2004), suggests that GGF2 might rekindle endogenous processes associated with rehabilitation long after stroke injury has occurred. The results provided by Iaci et al. in this issue are truly intriguing, and as true for many signicant scientic results, they generate more questions and experiments than they answer. Even basic issues like repair and reorganization of diffuse cell and axonal injury/loss, neurogenesis, angiogenesis, synaptogenesis, etc. now need to be addressed with experimental data. 4. Speculation: growth factors and stem cells It is interesting to speculate on what might be, at least in part, involved in GGF2. Perhaps it is stimulating endogenous processes, as do stem-cell-like interventions. For example, in the rat, bone marrow stromal cells can facilitate recovery even when administered a month after stroke injury (Shen et al., 2007) and effects on improving function can persist for a year (Liu et al., 2007). They can also promote increase growth factor expression, factors that can additionally participate in the process of brain restoration (Mahmood et al., 2004; Wakabayashi et al., 2010). Growth factors can act together with stromal cells to promote neural regeneration and restoration of function (Bhang et al., 2007; Cho et al., 2010; Kim et al., 2006). 5. Conclusions The additional data demonstrating signicant GGF2 protection when administered after transient stroke, when administered prior to permanent stroke, and the demonstration of direct GGF2 neuronal protection (Li et al., 2007; Xu et al., 2005, 2006), suggest many opportunities for this protein. If GGF2 is protective against other types of brain injury (e.g., especially hemorrhagic stroke) and does not interact negatively with tPA thrombolysis to increase hemorrhagic conversion or mortality (Ehrenreich et al., 2009; Jia et al., 2010), then the opportunity is signicant. The indications could be both for A) immediate use to protect, and B) continued use

Please cite this article in press as: Barone, F.C., Post-stroke pharmacological intervention: Promoting brain recovery from injury in the future, Neuropharmacology (2010), doi:10.1016/j.neuropharm.2010.08.016

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to restore with no safety risk. If it improves the use of tPA (e.g., extends the time period for safe use), then one might have in hand the golden chalice of stroke intervention. Similar to the targeting the penumbra (i.e., the salvageable brain region outside the ischemic core that dies more rapidly in ischemia) as a neuroprotection strategy in stroke, restorative strategies now and into the future focus on the neurovascular reorganization within the penumbra (i.e., actually peri-infarct areas after injury has occurred), including functional connections from the periinfarct to other brain areas that can take over function lost due to injury (Lo, 2008; Ohab et al., 2006; Liu et al., 2010). In this era of increasing molecular and genetic sophistication, unexpected mechanistic break-throughs are likely to occur. As the authors themselves indicate, if GGF2 delayed intervention efcacy on improved outcome is conrmed in other models of stroke/brain injury, including additional data on restorative mechanism(s) and safety, we might look forward to evaluation of GGF2 as a clinical candidate in the future. Its a long way to go from here, but these data are exciting and make one consider the possibilities and, of course, the potential signicance to patients.

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