Highlights
- •Tβ4 improves neurological outcome in a rat model of embolic stroke at 2 & 12 mg/kg.
- •The calculated optimal dose that provides neurological improvement is 3.75 mg/kg.
- •Tβ4 promotes oligodendrogenesis.
- •These results provide preclinical data for human clinical trials.
Abstract
Background
Thymosin β4 (Tβ4) is a 5 K actin binding peptide. Tβ4 improves neurological outcome in a rat model of embolic
stroke and research is now focused on optimizing its dose for clinical trials. The
purpose of this study was to perform a dose–response study of Tβ4 to determine the
optimal dose of neurological improvement in a rat model of embolic stroke.
Methods
Male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo).
Rats were divided into 4 groups of 10 animals/group: control, 2, 12 and 18 mg/kg. Tβ4 was administered intraperitoneally 24 h after MCAo and then every 3 days for 4 additional doses in a randomized controlled fashion. Neurological tests
were performed after MCAo and before treatment and up to 8 weeks after treatment. The rats were sacrificed 56 days after MCAo and lesion volumes measured. Generalized estimating equation was used
to compare the treatment effect on long term functional recovery at day 56. A quartic
regression model was used for an optimal dose determination.
Results
Tβ4 significantly improved neurological outcome at dose of 2 and 12 mg/kg at day 14 and extended to day 56 (p-values <0.05). The higher dose of 18 mg/kg did not show significant improvement. The estimated optimal dose of 3.75 mg/kg would provide optimal neurological improvement.
Conclusions
This study shown that Tβ4 significantly improved the long term neurological functional
recovery at day 56 after MCAo with an optimal dose of 3.75 mg/kg. These results provide preclinical data for human clinical trials.
Abbreviations:
Tβ4 (thymosin beta 4), EAE (experimental autoimmune encephalomyelitis), OPCs (oligodendrocyte progenitor cells), SVZ (subventricular zone), MCAo (middle cerebral artery occlusion), OL (mature oligodendrocytes), rt-PA (recombinant tissue plasminogen activator), CCA (common carotid artery), ECA (external carotid artery), ICA (internal carotid artery), IP (intraperitoneally), BrdU (5-bromo-2′-deoxyuridine), ART (adhesive-removal test), mNSS (modified Neurological Severity Score), FFT (foot fault test), MCID (microcomputer imaging device), NG-2 (chondroitin sulfate proteoglycan), APC (CC1) (adenomatous polyposis coli), MBP (myelin basic protein), GEEs (generalized estimation equations), NOEL (no observed effect level)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair.Nature. 2004; 432: 466-472
- Empirical model building and response surfaces.John Wiley & Sons, New York1987
- Animal models of neurological deficits: how relevant is the rat?.Nat Rev Neurosci. 2002; 3: 574-579
- Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats.Neuroscience. 2006; 141: 737-744
- Development of thymosin beta4 for treatment of patients with ischemic heart disease.Ann N Y Acad Sci. 2007; 1112: 385-395
- Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.Lancet Neurol. 2009; 8: 355-369
- Why does remyelination fail in multiple sclerosis?.Nat Rev Neurosci. 2002; 3: 705-714
- Remyelination in the CNS: from biology to therapy.Nat Rev Neurosci. 2008; 9: 839-855
- The biology of CNS remyelination: the key to therapeutic advances.J Neurol. 2008; 255: 19-25
- Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.N Engl J Med. 2008; 359: 1317-1329
- US geographic distribution of rt-PA utilization by hospital for acute ischemic stroke.Stroke. 2009; 40: 3580-3584
- Global test statistics for treatment effect of stroke and traumatic brain injury in rats with administration of bone marrow stromal cells.J Neurosci Methods. 2003; 128: 183-190
- Thymosin beta4 accelerates wound healing.J Invest Dermatol. 1999; 113: 364-368
- Researchers hope measuring performance will improve stroke care and prevention.JAMA. 2010; 303: 17-18
- Thymosin beta4 improves functional neurological outcome in a rat model of embolic stroke.Neuroscience. 2010; 169: 674-682
- The role of SVZ-derived neural precursors in demyelinating diseases: from animal models to multiple sclerosis.J Neurol Sci. 2008; 265: 26-31
- Cerebral white matter is highly vulnerable to ischemia.Stroke. 1996; 27 ([discussion 1647]): 1641-1646
- A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers.Ann N Y Acad Sci. 2010; 1194: 223-229
- SAS Institute I User's guide SAS/STAT 9.2. SAS Institute, Inc., Cary, NC2010
- Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization.Nature. 2007; 445: 177-182
- Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.N Engl J Med. 1995; 333: 1581-1587
- Treatment of traumatic brain injury with thymosin beta(4) in rats.J Neurosurg. 2011; 114: 102-115
- Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis.Neuroscience. 2009; 164: 1887-1893
- Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat.PLoS One. 2010; 5: e11016
- Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats.Stroke. 2002; 33: 2675-2680
- A rat model of focal embolic cerebral ischemia.Brain Res. 1997; 766: 83-92
- Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic.Lancet Neurol. 2009; 8: 491-500
Article info
Publication history
Published online: July 10, 2014
Accepted:
July 1,
2014
Received in revised form:
June 30,
2014
Received:
April 10,
2014
Identification
Copyright
© 2014 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
