Mobilization of Stem Cells Using G-CSF for Acute Ischemic Stroke: A Randomized Controlled, Pilot Study

SAGE-Hindawi Access to Research Stroke Research and Treatment Volume 2011, Article ID 283473, 7 pages doi:10.4061/2011/283473 Clinical Study Mobilization of Stem Cells Using G-CSF for Acute Ischemic Stroke: A Randomized Controlled, Pilot Study Kameshwar Prasad,1 Amit Kumar,1 Jitendra Kumar Sahu,1 M. V. P. Srivastava,1 Sujata Mohanty,2 Rohit Bhatia,1 Shailesh B. Gaikwad,3 Achal Srivastava,1 Vinay Goyal,1 Manjari Tripathi,1 Chandrashekar Bal,4 and Nalini Kant Mishra3 1 Department of Neurology, Room No. 704, Neurosciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India 2 Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India 3 Department of Neuro-Radiology, All India Institute of Medical Sciences, New Delhi 110029, India 4 Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi 110029, India Correspondence should be addressed to Kameshwar Prasad, Received 14 April 2011; Revised 18 July 2011; Accepted 19 July 2011 Academic Editor: Stefan Schwab Copyright © 2011 Kameshwar Prasad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. There is emerging evidence to support the use of granulocyte colony-stimulating factor (G-CSF) therapy in patients with acute ischemic stroke. Aims. To explore feasibility, safety, and preliminary efficacy of G-CSF therapy in patients with acute ischemic stroke. Patients and Method. In randomized study, 10 patients with acute ischemic stroke were recruited in 1 : 1 ratio to receive 10 µg/kg G-CSF treatment subcutaneously daily for five days with conventional care or conventional treatment alone. Efficacy outcome measures were assessed at baseline, one month, and after six months of treatment included Barthel Index (BI), National Institute of Health Stroke Scale, and modified Rankin Scale. Results. One patient in G-CSF therapy arm died due to raised intracranial pressure. No severe adverse effects were seen in rest of patients receiving G-CSF therapy arm or control arm. No statistically significant difference between intervention and control was observed in any of the scores though a trend of higher improvement of BI score is seen in the intervention group. Conclusion. Although this study did not have power to examine efficacy, it provides preliminary evidence of potential safety, feasibility, and tolerability of G-CSF therapy. Further studies need to be done on a large sample to confirm the results. 1. Introduction Stroke is an important cause of mortality and morbidity worldwide [1]. Despite recent advances in antithrombotic treatment, poststroke disability has significant economic and social burden. As brain has limited capacity to regenerate, there is the need to develop therapeutic strategies to enhance neuroprotection and repair. Autologous stem-cell transplantation has been tried but has limited due to unproven efficacy and lack of available facility widespread [2]. Currently, few treatments exist for acute stroke, comprising mainly aspirin and thrombolytic drugs which have poor availability in the developing countries and very narrow time window for its intervention. A clear need exists to identify new drugs. Granulocyte colony stimulating-factor (G-CSF) is a cytokine that acts on hematopoietic stem (CD34+ ) cells and stimulates proliferation, maturation, and survival of the neutrophilic granulocyte lineage. It is widely employed to mobilize bone marrow stem cells in patients with leukaemia treated with bone marrow transplantation and chemotherapy-induced neutropenia for last two decades [3]. Since Schäbitz et al. [4] observed infarct size-reducing capabilities of G-CSF in animal stroke model, a number of preclinical investigations were initiated to explore its neuroprotective abilities. In later experimental studies of cerebral ischemia, G-CSF was found to be neuroprotective via different mechanisms, including mobilization of haemopoietic stem cells, antiapoptosis, neuronal differentiation, angiogenesis, and anti-inflammation [5, 6]. These properties are particularly significant in view of apoptosis, 2 and inflammation has implication in the pathophysiology of cerebral ischemic injury. In virtue of the above properties, it was speculated that G-CSF not only inhibits neuron death, but also generates new neuronal tissue formation. The observation of G-CSF’s effect on mobilization of stem cells from the bone marrow initiated explorations of its potential benefit in stroke with the assumption that mobilized stem cells may home into the injured brain. Meta-analysis from the animal studies suggested that G-CSF both reduces infarct size and enhances functional recovery, and its effect is presumably dose dependent [7]. Three small clinical trials investigated the safety and feasibility and efficacy of stem cell mobilization by G-CSF in 7, 24, and 44 patients at different doses of G-CSF with acute ischemic stroke patients, respectively [8–10]. In all studies, G-CSF therapy appeared to be safe and reasonably well tolerated. Summary of G-CSF published studies in stroke patients are given in Table 1. There are several trials of G-CSF therapy in stroke ongoing across the world. Results of these trials will be helpful in knowing the efficacy of G-CSF therapy in stroke. Building on preclinical and clinical data suggesting functional and survival benefit using granulocyte colonystimulating factor (G-CSF) in this fashion, we undertook a single centre, randomized, open-label pilot trial in patients with acute ischemic stroke. Moreover, the therapy is less invasive, relatively inexpensive (compared to rt-PA), ethically acceptable, and has long therapeutic window. The aim of the present study was to assess the safety and efficacy of G-CSFs at 10 µg/kg G-CSF in patients with acute ischemic stroke and to assess the effect on circulating stem cell and blood cell counts. 2. Methods 2.1. Participants. All patients with acute ischemic stroke attending the neurology services at All India Institute of Medical Sciences, New Delhi, between January 2008 and May 2008, were screened for eligibility of this study. Patients with stroke (defined as rapidly developing clinical symptoms and/or signs of focal loss of cerebral function, with symptoms lasting more than 24 hours with no apparent cause other than that of vascular origin) were considered eligible if they fulfilled all of the following: age between 30 and 75 years, within seventh day from onset, computed tomography and/or magnetic resonance imaging scan of the brain showing no haematoma, and relevant lesions within the middle cerebral artery territory, Glasgow coma scale (GCS) score above eight (eye and motor score of more than six in patients with aphasia), Barthel index (BI) score of 55 or less, National Institute of health stroke Scale (NIHSS) score betw (...truncated)