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Discov Med. 2010 November ; 10(54): 434–442.
Neurorestorative Treatments for Traumatic Brain Injury
Ye Xiong1, Asim Mahmood1, and Michael Chopp2,3,*
1 Department of Neurosurgery, Henry Ford Health System, 2799 West Grand Boulevard, Detroit,
MI 48202, USA
2 Department of Neurology, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI48202, USA 3 Department of Physics, Oakland University, Rochester, MI 48309, USA Abstract
Traumatic brain injury (TBI) remains a major cause of death and permanent disability worldwide,especially in children and young adults. A total of 1.5 million people experience head trauma each year in the United States, with an annual economic cost exceeding $56 billion. Unfortunately,almost all Phase III TBI clinical trials have yet to yield a safe and effective neuroprotectivetreatment, raising questions regarding the use of neuroprotective strategies as the primary therapyfor acute brain injuries. Recent preclinical data suggest that neurorestorative strategies thatpromote angiogenesis (formation of new blood vessels from pre-existing endothelial cells), axonalremodeling (axonal sprouting and pruning), neurogenesis (generation of new neurons) andsynaptogenesis (formation of new synapses) provide promising opportunities for the treatment ofTBI. This review discusses select cell-based and pharmacological therapies that activate andamplify these endogenous restorative brain plasticity processes to promote both repair andregeneration of injured brain tissue and functional recovery after TBI.
angiogenesis; functional recovery; neurogenesis; plasticity; synaptogenesis; traumatic brain injury Introduction
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide,particularly among the young. Neuroprotection is an important strategy for the treatment ofTBI (Narayan et al., 2002). To date, no effective neuroprotective agents have been identifiedfrom TBI clinical trials. The disappointing clinical trials may be due to variability intreatment approaches and heterogeneity of the population of TBI patients. Anotherimportant aspect is that most clinical trial strategies have used drugs that target a singlepathophysiological mechanism, although many mechanisms are involved in secondaryinjury after TBI. Recent research has focused increasingly on multifunctional agents thattarget multiple injury mechanisms, particularly those that occur later after the insult (Stoicaet al., 2009). Targeting multiple injury mechanisms that contribute to the secondary injurycascade may increase successful clinical trial outcomes.
Recent preclinical studies have revealed that TBI induces neurogenesis, axonal sprouting,and angiogenesis (Lu et al., 2004a; Lu et al., 2005; Oshima et al., 2009; Richardson et al., *Correspondence should be addressed to: Michael Chopp, Ph.D., Department of Neurology, Henry Ford Health System, 2799 WestGrand Boulevard, Detroit, MI 48202, Tel: 313-916-3936, Fax: 313-916-1318, email@example.com.
2007; Xiong et al., 2010a; Zhang et al., 2010), which may contribute to the spontaneousfunctional recovery. Agents and treatments that promote these neurorestorative processes have been demonstrated to improve functional recovery after brain injury (Zhang andChopp, 2009). However, clinical trials in TBI have primarily targeted neuroprotection, andtrials directed specifically at neurorestoration have not been conducted. The promotion ofneurorestorative processes may be a potential therapy for TBI. We review select cell-basedand pharmacological therapies that enhance endogenous restorative brain plasticityprocesses to improve functional recovery after TBI.
Throughout life, neurogenesis occurs in all mammalian brains in the subventricular zone(SVZ) of the lateral ventricle and in the dentate gyrus subgranular zone (SGZ) of thehippocampus (Zhao et al., 2008). Newly generated neurons originate from neural stem cells(NSCs) in the adult brain. NSCs are self-renewing multipotent cells that generate glial andneuronal cells (Zhao et al., 2008). Granule neurons in the dentate gyrus of the hippocampuscontinuously die, and the neural stem/progenitor cells in the SGZ may proliferate tomaintain a constant cell number in the dentate gyrus. Moreover, newly generated neurons inthe dentate gyrus are capable of projecting axons into the CA3 region of the hippocampus innormal brains in rodents (Hastings and Gould, 1999). TBI induces hippocampal cellproliferation (Kernie et al., 2001; Lu et al., 2005; Xiong et al., 2008), and the vast majority of the newly generated cells in the SGZ that survive for 10 weeks after TBI differentiate intomature neurons (Sun et al., 2007). Newborn neurons extend axonal projections into the CA3region as early as 2 weeks after TBI (Emery et al., 2005), which may contribute to cognitiverecovery observed in rats that have experienced a TBI. In the normal adult brain, SVZ-derived neuroblasts migrate along the rostral migratory stream to the olfactory bulb, wherethese cells differentiate into interneurons to replace those that have died. After corticalinjuries, a portion of neuroblasts generated in the SVZ migrate to injured areas instead of therostral migratory stream. Following TBI, neuroblasts migrating from the SVZ candifferentiate into neurons and glia (Kernie et al., 2001).
The adult central nervous system (CNS) vasculature is extremely stable under physiologicalconditions, but is activated after injury (Greenberg and Jin, 2005). Adult vascularremodeling includes angiogenesis by mature endothelial cells (that is, the formation of newcapillaries from pre-existing vessels) and vasculogenesis (de novo formation of bloodvessels when there are no pre-existing ones) by endothelial progenitor cells (EPCs). EPCsare present in the bone marrow and peripheral blood, and mobilize to the latter following TBI (Guo et al., 2009). There is a substantial increase in vasculogenesis following TBI(Morgan et al., 2007). Pharmacological agents such as erythropoietin (EPO) and statinsincrease the number, mobilization and functional activity of EPCs (Besler et al., 2008).
EPO, statins, bone marrow stromal cells (MSCs), and thymosin beta4 promote angiogenesisand improve functional recovery in rats after TBI (Chopp and Li, 2002; Lu et al., 2004b; Luet al., 2007b; Mammis et al., 2009; Wible and Laskowitz, 2010; Xiong et al., 2010a; Xionget al., 2010b). The strategies for mobilization and/or transplantation of EPCs or treatmentwith angiogenesis-enhancing agents may emerge as promising approaches for the treatmentof TBI.
Coupling of Neurogenesis and Angiogenesis
Neurovascular niches within the CNS consist of endothelial cells, pericytes, neurons andglial cells, as well as growth factors and extracellular matrix proteins surrounding theendothelium (Lok et al., 2007). The neurovascular niches provide microenvironments for Discov Med. Author manuscript; available in PMC 2011 November 1.
NSCs in the adult brain; newly generated, immature neurons are closely associated with theremodeling vasculature. The generation of new vasculature facilitates coupled neurorestorative processes including neurogenesis and synaptogenesis, which improvefunctional recovery (Li and Chopp, 2009; Zhang and Chopp, 2009). Angiogenesis andneurogenesis may play a significant role in mediating functional recovery followingexperimental TBI (Chopp et al., 2008; Li and Chopp, 2009; Lu et al., 2005; Wu et al.,2008b; Xiong et al., 2008; Zhang et al., 2009b). Neurorestorative agents that increaseangiogenesis and neurogenesis have been shown to improve functional outcome followingbrain injury (Zhang et al., 2009b; Zhang and Chopp, 2009). Vascular endothelial cells withinthe neurovascular niche affect neurogenesis directly via contact with neural progenitor cellswhile soluble factors from the vascular system that are released into the CNS enhanceneurogenesis via paracrine signaling (Yang et al., 2010). A better understanding of precisemolecular mechanisms in the neurovascular niches will be important for developing novelangiogenic and neurogenic therapies for brain injuries.
The CNS has a limited capacity to regenerate after injury. Axonal sprouting from survivingneurons may be associated with spontaneous motor recovery over time after TBI (Oshima etal., 2009; Smith et al., 2007). Spontaneous pericontusional axon sprouting takes place within1–2 weeks after TBI, which is induced by controlled cortical impact (CCI) in the adult rat but ultimately fails due to an axonal growth-inhibitory environment (Harris et al., 2010). Toreduce pericontusional growth-inhibitory chondroitin sulphate proteoglycans, acute infusionof chondroitinase ABC into the site of the cortical contusion was performed, whichenhanced and prolonged the sprouting response and reduced unskilled limb use deficits(Harris et al., 2010). In principle, a treatment that promotes axonal plasticity could bebeneficial to functional recovery after brain injury (Smith et al., 2007). The corticospinaltract is a major fiber bundle arising from layer V pyramidal neurons of the frontal motorcortex and connects via the corticospinal or pyramidal tracts to contralateral motor neuronsof the spinal cord to control voluntary movements. Collateral sprouting of the unlesionedcorticospinal tract at the cervical spinal cord and neuromotor functional recovery wereobserved following unilateral TBI in mice (Oshima et al., 2009). In a full-thickness lesion ofthe forelimb region of the sensorimotor cortex, skilled paw-reaching behavior, a task thatrequires corticospinal function, was only partially recovered by 4 weeks. Inosine infusedinto the lateral ventricles for 4 weeks produced an almost complete recovery of skilled paw-reaching ability, which is associated with sprouting of the uninjured corticospinal axonsacross the midline into the red nucleus and cervical cord of the lesioned pathway (Smith etal., 2007).
Brain function relies on communication among neurons through highly specialized contacts(that is, the synapses) and synaptic dysfunction plays a critical role in injury-induced defectsof the CNS. In response to a CNS injury, surviving neurons reorganize their connections andform new synapses to replace those lost caused by the lesion (Becher et al., 1999).
Synaptophysin (SYP), a neuronal marker of synaptogenesis, is an integral transmembraneprotein component of presynaptic vesicles and is widely expressed in neurons. CCI results inthe loss of specific neurons in the CA3 subfield of the ipsilateral hippocampus, resulting inpartial loss of afferents to the CA1 subfield; the CNS compensates for deafferentiation byinitiating synaptogenesis capable of restoring some of the lost synaptic contacts (Scheff etal., 2005). After CCI, the density of SYP signals in the injury boundary zone was less thanthat of the intact cortical area (Lu et al., 2004a). After treatment with atorvastatin, thedensity significantly increased in this area compared to the control rats (Lu et al., 2004a).
Discov Med. Author manuscript; available in PMC 2011 November 1.
Atorvastatin may protect synapses from the impact or induce synaptogenesis in theboundary zone. Almost no SYP-positive signals were detected in the stratum lucidum and some weak signals were observed in the pyramidal cell layer. After atorvastatin treatment,intense SYP signals were found in the pyramidal cell layer as well as in the stratum lucidum(Lu et al., 2004a). Atorvastatin-induced synaptogenesis may contribute to reduction in theneurological functional deficits.
Bone Marrow Stromal Cells
Although human embryonic stem cells (hESCs) or fetal tissues are suitable sources for cell-based therapies, their clinical application is limited by both ethical considerations and otherpractical challenges including tumorigenicity, cell viability and antigenic compatibility.
Reprogramming differentiated cells generates induced pluripotent stem cells (iPSCs) thatresemble embryonic stem cells (Yamanaka, 2007). These iPSCs avoid the ethical issues andremove the major roadblock of immune rejection associated with the clinical use of hESCs,as well as potentially generate patient-specific cells for cell-replacement therapy. However,the safety and therapeutic applications of iPSCs and iPSC-derived cells must be rigorouslytested in appropriate animal models before advancing to any clinical trial. The mostimportant issue with iPSCs is potential tumorigenicity. Even with improvements in thevirus-free and transgene-free reprogramming technologies, the cancer-causing possibility ofthe derived “safe” iPSCs/derivatives still needs to be evaluated in animal models before their clinical application for regenerative treatment.
Bone marrow stromal cells (MSCs) are a mixed cell population, including stem andprogenitor cells, and are a promising source of cell-based therapy for TBI, since they can beeasily isolated from many tissues and expanded in culture from patients without ethical andimmune rejection problems (Chopp and Li, 2002). When grafted into the lateral ventricles ofneonatal mouse brains, mouse MSCs migrated and differentiated into olfactory bulb granulecells and periventricular astrocytes (Deng et al., 2006). Systematically infused rat MSCsmigrated into injured rat brains and survived (Lu et al., 2001). Some of the implanted MSCsexpressed cell markers for neurons and astrocytes. Expression of the chemokine stromal-cell-derived factor-1 was significantly increased in the lesion boundary zone after braininjury induced by ischemia (Shen et al., 2007). The stromal-cell-derived factor-1 receptor,CXC-chemokine receptor-4, was expressed in MSCs both in vitro and in vivo (Shen et al.,2007). The interaction of stromal-cell-derived factor-1 with CXC-chemokine receptor-4 maycontribute to the trafficking of transplanted MSCs into the injured brain (Itoh et al., 2009;Shen et al., 2007). Direct implantation (6 h post injury) of MSCs enhances neuroprotectionvia activation of resident NSC nuclear factor B activity leading to an increase in interleukin-6 production and decrease in apoptosis (Walker et al., 2010). The delayedadministration (24 h or 1 week following injury) of MSCs also significantly improvedfunctional outcome in rodents following TBI (Chopp and Li, 2002; Chopp et al., 2009; Lu etal., 2001; Mahmood et al., 2004b; Mahmood et al., 2005; Mahmood et al., 2006).
MSCs secrete various growth factors, including brain-derived neurotrophic factor (BDNF),vascular endothelial growth factor (VEGF) and bFGF (basic fibroblast growth factor), andincrease the levels of these factors in the brain (Chopp and Li, 2002; Mahmood et al.,2004a). MSCs also induce intrinsic parenchymal cells to produce these growth factors(Mahmood et al., 2004a). After MSC transplantation, these neurotrophic/growth factorsenhance angiogenesis and vascular stabilization in the lesion boundary zone where themajority of MSCs that survive in the brain are located (Mahmood et al., 2006). Thesegrowth factors also promote neurogenesis in vitro and in vivo (Jin et al., 2002; Lee et al.,2002; Yoshimura et al., 2003). In rodent TBI models, MSCs not only increased vasculardensity in the lesion boundary zone and hippocampus (Qu et al., 2008), but also enhanced Discov Med. Author manuscript; available in PMC 2011 November 1.
neurogenesis in the SGZ and SVZ (Mahmood et al., 2004b). Delayed (4 days after TBI)treatment with MSCs alone did not reduce lesion volume, whereas MSCs seeded in collagen scaffolds significantly reduced lesion volume, enhanced the migration of MSCs into thelesion boundary zone, and significantly improved spatial learning and sensorimotor function(Lu et al., 2007a). Even more delayed (7 days post injury) transplantation of MSCs or MSCsseeded in scaffolds improved spatial learning and sensorimotor function, enhancedangiogenesis in the injured cortex and the ipsilateral hippocampus and increasedtranscallosal neural fibers in the injured cortex (Xiong et al., 2009). The significanttherapeutic benefits of MSCs are not attributed to the few MSCs that differentiate intoneural cells (Lu et al., 2001). However, MSCs appear to act as neurotrophic/growth factorgenerators and inducers to promote brain functional recovery via angiogenesis,neurogenesis, synaptogenesis and axonal remodeling (Chopp and Li, 2002; Chopp and Li,2006). MSCs (or neural stem/precursor cells)-seeded scaffolds may be a new and effectivestrategy for treatment of TBI.
The safety and feasibility of treatment with autologous MSCs were assessed in sevenpatients with TBI (Zhang et al., 2008). In this trial, no toxicity related to the cell therapy wasobserved within the 6-month follow-up period. A safety study of autologous stem celltreatment in children with TBI has also been completed (ClinicalTrials.gov, Identifier:NCT00254722); however, no data are available. This study should determine if bone marrow harvest and re-infusion is safe in children after severe TBI.
EPO stimulates the maturation, differentiation and survival of hematopoietic progenitor cellsto maintain erythropoiesis and has been widely used for treatment of anemia. Although lowlevels of EPO and EPO receptors exist in normal adult brains, increased expression of EPOand the EPO receptors is found in neurons, neural progenitor cells, glial cells, andendothelial cells in response to injury (Grasso et al., 2004). EPO (5000 U/kg ip) wasdemonstrated to cross the blood-brain barrier and to protect against brain injury in rats(Brines et al., 2000; Wang et al., 2004). Acute EPO administration (within 6-h post-TBI)provides neuroprotection (that is, decreased lesion volume and cell loss) as well as enhancesneurogenesis, and subsequently improves sensorimotor and spatial learning functions in ratand mouse models (Brines et al., 2000; Cherian et al., 2007; Xiong et al., 2008; Zhang et al.,2009b). Delayed administration of EPO (5000 U/kg, ip for 14 days) from day 1 followingTBI in rats significantly increased dentate gyrus neurogenesis and improved spatial memory(Lu et al., 2005). Post-TBI treatment (6-h or 24-h post-injury) with EPO (5000 U/kg)significantly increased the expression of BDNF and improved spatial learning following injury in rats (Mahmood et al., 2007b). Our recent studies demonstrate that a multiple-dosetreatment with EPO (5000 U/kg/day for 3 days initiated at day 1 post-injury) is moreeffective than a single-dose EPO therapy in improving functional recovery in rats after TBI(Xiong et al., 2010a). Treatment with EPO also contributes to neurovascular remodeling,leading to improved neurobehavioral outcomes following TBI (Xiong et al., 2010a; Zhang etal., 2009b). EPO enhances VEGF secretion from neural progenitor cells; the treatment ofsuch cells with EPO leads to the upregulation of VEGF receptor 2 expression in cerebralendothelial cells, promoting angiogenesis (Wang et al., 2008).
Our previous study showed that delayed (24 h post injury) EPO treatment improvesneurological functional recovery without reducing lesion volume after TBI (Xiong et al.,2010a). In addition to its effects on neurogenesis and angiogenesis, EPO may improveneurological recovery partially through enhancement of axonal plasticity. Axonal sproutingfrom the intact corticospinal tract was increased in the denervated side of the gray matter ofboth cervical and lumbar levels of the spinal cord at day 35 after TBI. However, the Discov Med. Author manuscript; available in PMC 2011 November 1.
corticospinal tract axonal sprouting was significantly enhanced at both cervical and lumbarspinal cord in the EPO-treated TBI animals (Zhang et al., 2010). The contralesional corticospinal tract axonal sprouting was highly and positively correlated with sensorimotorrecovery after TBI, suggesting axonal sprouting induced by EPO treatment may contributeto functional recovery after TBI.
In a small clinical trial for treating stroke with EPO, intravenous administration of EPO iswell tolerated in acute ischemic stroke and associated with an improvement in clinicaloutcome at one month (Ehrenreich et al., 2002). However, in a recent large clinical trial ofstroke, EPO treatment has not resulted in benefits (increasing higher mortality compared toplacebo controls) (Ehrenreich et al., 2009). Combination of tissue plasminogen activatorwith EPO may be one of the important factors for this failed clinical trial, because a verylarge number of EPO-treated stroke patients also received tissue plasminogen activatortreatment and combination of EPO with tissue plasminogen activator has been demonstratedto cause detrimental effects in animal models of stroke (Jia et al., 2010).
A phase III trial of EPO in patients with TBI has been planned (ClinicalTrials.gov,NCT00987454). A phase II trial investigating the safety of treatment with Darbepoetin Alfa(a long-acting form of EPO) in patients with severe TBI is ongoing (ClinicalTrials.gov,NCT00375869). A phase II/III trial to investigate the early administration of EPO to TBIpatients is ongoing (ClinicalTrials.gov, NCT00260052). The high doses of EPO used for the treatment of stroke and TBI significantly increased hematocrit (Mahmood et al., 2007b;Xiong et al., 2008), which may cause adverse vascular effects such as deep venousthrombosis (Lapchak, 2008). However, non-hematopoietic EPO analogs, such as thecarbamylated form of EPO (CEPO), are as effective as hematopoietic EPO inneuroprotection and are not associated with the hematopoietic side effects (Lapchak, 2008;Mahmood et al., 2007b), indicating their potential application to TBI therapy. The optimalEPO dose, dosing interval, and number of doses for reducing brain injury that promoteneurorestoration and improve functional recovery have not been fully investigated after TBI.
The EPO doses for the TBI clinical trials are based on stroke trials. Lack of preclinical dataon these important aspects highlights the importance of fully evaluating EPO and its analogsfor both acute protection and chronic restoration of function after TBI.
Statins, inhibitors of cholesterol biosynthesis used to lower cholesterol levels, induceangiogenesis, neurogenesis and synaptogenesis, and enhance functional recovery followingTBI in rats (Lu et al., 2004a; Lu et al., 2004b; Lu et al., 2007b; Wu et al., 2008b). Thesebeneficial effects of statins are independent of cholesterol-lowering action. Beneficial effects of simvastatin may be mediated through activation of Akt, Forkhead transcription factor 1and nuclear factor– B signaling pathways, which suppress the activation of caspase-3 andapoptotic cell death, and thereby, lead to neuronal function recovery after TBI (Wu et al.,2008a). Simvastatin activates the Akt-mediated signaling pathway, subsequentlyupregulating the expression of growth factors and inducing neurogenesis in the dentategyrus of the hippocampus, thereby leading to restoration of cognitive function after TBI inrats (Wu et al., 2008b). In addition, simvastatin treatment provided long-lasting (3 month)functional improvement following TBI in rats (Mahmood et al., 2009). The protectivemechanisms of statins may be partly attributed to a reduction in the inflammatory responsefollowing TBI (Li et al., 2009). When administered in combination with MSCs in a ratmodel of TBI, atorvastatin increased MSC access and/or survival within the injured brainand enhanced functional recovery compared with either MSC or atorvastatin monotherapy(Mahmood et al., 2007a), suggesting that statins might be used in conjunction with MSCtransplantation for treating neurological disorders and injuries.
Discov Med. Author manuscript; available in PMC 2011 November 1.
Given the wide use, favorable safety profile and positive clinical data for statins, the rareoccurrence of serious adverse events and the extensive available preclinical data demonstrating neuroprotection and neurorestoration (Wible and Laskowitz, 2010), furtherclinical trials are warranted to determine the neuroprotective and neurorestorative propertiesof statins following TBI. The effect of rosuvastatin on TBI-induced cytokine change isongoing in a phase I/II trial (ClinicalTrials.gov, NCT00990028).
Thymosin Beta 4
Thymosin beta 4 (T 4), a polypeptide of 43-amino acids, was first isolated from bovinethymus tissue and subsequently found to exist in all mammals studied. The majorintracellular function of T 4 is G-actin-sequestration, which is necessary for cell motilityand organogenesis (Crockford, 2007). Recent studies demonstrate that T 4 is amultifunctional peptide. It inhibits inflammation and apoptosis, and promotes tissue repair inskin, cornea, and heart (Morris et al., 2010b). T 4 is an essential paracrine factor of EPCs,and T 4 promotes angiogenesis after ischemic injury (Smart et al., 2007). Safety, tolerabilityand efficiency of T 4 are being evaluated in clinical patients with acute myocardialinfarction (Crockford, 2007).
T 4 plays a critical role in many cellular processes including mobility, axonal path-finding,neurite formation, proliferation and neuronal survival (Morris et al., 2010b; Sun and Kim, 2007). Our recent study demonstrates that T 4 improves neurological functional recovery inmice with experimental autoimmune encephalomyelitis (Zhang et al., 2009a) and in ratswith embolic stroke (Morris et al., 2010a). T 4 is a potential treatment for TBI. T 4 (6 mg/kg) was administered ip starting at day 1 and then every 3 days for an additional 4 doses tothe TBI rats (Xiong et al., 2010b). Neurological functional recovery was evaluated. Animalswere euthanized 35 days after injury and brain sections were stained forimmunohistochemistry to assess angiogenesis, neurogenesis, and oligodendrogenesis afterT 4 treatment. Delayed T 4 treatment did not affect lesion volume but significantly reducedhippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex andhippocampus, increased oligodendrogenesis in the CA3 region, and significantly improvedsensorimotor functional recovery and spatial learning compared to the saline treatment.
These data demonstrate that administration of T 4 significantly improves histological andfunctional outcomes in rats with TBI, indicating that T 4 has considerable therapeuticpotential in TBI patients. Further investigation of T 4 is warranted for the treatment of TBI.
TBI induces angiogenesis, axonal remodeling, and neurogenesis in preclinical studies.
Strategies that enhance these neurorestorative processes have been demonstrated to improvebrain functional recovery in experimental TBI. A better understanding of the relationshipbetween functional recovery and these processes will lead to novel therapeutic strategies forthe treatment of TBI. The cell-based and pharmacological therapies (for example, MSCs,EPO, CEPO, statins, T 4, alone or in combination) described in this review induceendogenous neurorestorative processes by increasing angiogenesis, axonal remodeling,neurogenesis and synaptogenesis, and consequently improve neurological functionalrecovery following TBI. However, several issues should be considered during the preclinicalstudies and clinical trials of these strategies in TBI. Prior to the translation of an agent or celltherapy into TBI clinical trials, sufficient preclinical data should be obtained from multipleexperiments, preferably in several brain injury models, on optimal administration routes,single dose versus multiple dose, bolus dose versus continuous infusion, dose-response, andtherapeutic windows. Extensive pharmacokinetic data for agents to treat injured brainsshould also be obtained, ensuring an adequate concentration in the brain tissue. In addition, Discov Med. Author manuscript; available in PMC 2011 November 1.
the effective progression of strategies into clinical trials may require multiple functionalagents including EPO, CEPO, statins, T 4, or combination therapies. These potential combinations include single agents (for example, small molecules or cytokines includingEPO, CEPO, T 4, VEGF) with cells (for example, MSCs, NSCs, iPSCs and geneticallymodified derivatives) or with other approaches (biomaterial scaffolds, physical or electricalstimulation). For the safety and efficacy, the interaction of agents used in combinationtherapy (such as EPO combined with tissue plasminogen activator) should be fullyaddressed in preclinical studies before their translation to clinical trials. Although it is stillimportant to further investigate neuroprotective treatments for TBI, an interesting novelresearch direction is the development of neurorestorative strategies that enhance axonalremodeling, angiogenesis, neurogenesis and synaptogenesis to improve functional recoveryof the injured brain.
The authors’ research was supported by NINDS grants RO1 NS62002 and PO1 NS042259.
Becher A, Drenckhahn A, Pahner I, Margittai M, Jahn R, Ahnert-Hilger G. The synaptophysin- synaptobrevin complex: a hallmark of synaptic vesicle maturation. J Neurosci. 1999; 19(6):1922– Besler C, Doerries C, Giannotti G, Luscher TF, Landmesser U. Pharmacological approaches to improve endothelial repair mechanisms. Expert Rev Cardiovasc Ther. 2008; 6(8):1071–1082.
[PubMed: 18793110] Brines ML, Ghezzi P, Keenan S, Agnello D, De Lanerolle NC, Cerami C, Itri LM, Cerami A.
Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc NatlAcad Sci U S A. 2000; 97(19):10526–10531. [PubMed: 10984541] Cherian L, Goodman JC, Robertson C. Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther. 2007; 322(2):789–794. [PubMed:17470644] Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002; 1(2):92– Chopp M, Li Y. Transplantation of bone marrow stromal cells for treatment of central nervous system diseases. Adv Exp Med Biol. 2006; 585:49–64. [PubMed: 17120776] Chopp M, Li Y, Zhang J. Plasticity and remodeling of brain. J Neurol Sci. 2008; 265(1–2):97–101.
Chopp M, Li Y, Zhang ZG. Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies. Stroke. 2009; 40(3 Crockford D. Development of thymosin beta4 for treatment of patients with ischemic heart disease.
Ann N Y Acad Sci. 2007; 1112:385–395. [PubMed: 17947592] Deng J, Petersen BE, Steindler DA, Jorgensen ML, Laywell ED. Mesenchymal stem cells spontaneously express neural proteins in culture and are neurogenic after transplantation. StemCells. 2006; 24(4):1054–1064. [PubMed: 16322639] Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, WesselTC, De Ryck M, Itri L, Prange H, et al. Erythropoietin therapy for acute stroke is both safe andbeneficial. Mol Med. 2002; 8(8):495–505. [PubMed: 12435860] Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A,Schwab S, Reichmann H, Schwendemann G, Dengler R, et al. Recombinant human erythropoietinin the treatment of acute ischemic stroke. Stroke. 2009; 40(12):e647–656. [PubMed: 19834012] Discov Med. Author manuscript; available in PMC 2011 November 1.
Emery DL, Fulp CT, Saatman KE, Schutz C, Neugebauer E, Mcintosh TK. Newly born granule cells in the dentate gyrus rapidly extend axons into the hippocampal CA3 region followingexperimental brain injury. J Neurotrauma. 2005; 22(9):978–988. [PubMed: 16156713] Grasso G, Sfacteria A, Cerami A, Brines M. Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go? Neuroscientist. 2004; 10(2):93–98. [PubMed:15070483] Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature. 2005; 438(7070):954–959.
Guo X, Liu L, Zhang M, Bergeron A, Cui Z, Dong JF, Zhang J. Correlation of CD34+ cells with tissue angiogenesis after traumatic brain injury in a rat model. J Neurotrauma. 2009; 26(8):1337–1344.
[PubMed: 19226208] Harris N, Mironova YA, Hovda D, Sutton RL. Chondroitinase ABC enhances pericontusion axonal sprouting but does not confer robust improvements in behavioral recovery. J Neurotrauma. 2010 inpress.
Hastings NB, Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells.
J Comp Neurol. 1999; 413(1):146–154. [PubMed: 10464376] Itoh T, Satou T, Ishida H, Nishida S, Tsubaki M, Hashimoto S, Ito H. The relationship between SDF-1alpha/CXCR4 and neural stem cells appearing in damaged area after traumatic brain injuryin rats. Neurol Res. 2009; 31(1):90–102. [PubMed: 19228460] Jia L, Chopp M, Zhang L, Lu M, Zhang Z. Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke. Stroke.
2010; 41(9):2071–2076. [PubMed: 20671252] Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002; 99(18):11946–11950. [PubMed: 12181492] Kernie SG, Erwin TM, Parada LF. Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice. J Neurosci Res. 2001; 66(3):317–326. [PubMed: 11746349] Lapchak PA. Carbamylated erythropoietin to treat neuronal injury: new development strategies. Expert Opin Investig Drugs. 2008; 17(8):1175–1186.
Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in thehippocampus of adult mice. J Neurochem. 2002; 82(6):1367–1375. [PubMed: 12354284] Li B, Mahmood A, Lu D, Wu H, Xiong Y, Qu C, Chopp M. Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury.
Neurosurgery. 2009; 65(1):179–185. [PubMed: 19574840] Li Y, Chopp M. Marrow stromal cell transplantation in stroke and traumatic brain injury. Neurosci Lett. 2009; 456(3):120–123. [PubMed: 19429146] Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, Van Leyen K, Lo EH. Cell-cell signaling in the neurovascular unit. Neurochem Res. 2007; 32(12):2032–2045. [PubMed: 17457674] Lu D, Goussev A, Chen J, Pannu P, Li Y, Mahmood A, Chopp M. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected totraumatic brain injury. J Neurotrauma. 2004a; 21(1):21–32. [PubMed: 14987462] Lu D, Mahmood A, Goussev A, Schallert T, Qu C, Zhang ZG, Li Y, Lu M, Chopp M. Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity,and enhancement of spatial learning in rats subjected to traumatic brain injury. J Neurosurg.
2004b; 101(5):813–821. [PubMed: 15540920] Lu D, Mahmood A, Qu C, Goussev A, Schallert T, Chopp M. Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma. 2005; 22(9):1011–1017. [PubMed: 16156716] Lu D, Mahmood A, Qu C, Hong X, Kaplan D, Chopp M. Collagen scaffolds populated with human marrow stromal cells reduce lesion volume and improve functional outcome after traumatic braininjury. Neurosurgery. 2007a; 61(3):596–602. [PubMed: 17881974] Discov Med. Author manuscript; available in PMC 2011 November 1.
Lu D, Mahmood A, Wang L, Li Y, Lu M, Chopp M. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurologicaloutcome. Neuroreport. 2001; 12(3):559–563. [PubMed: 11234763] Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, Mahmood A, Chen J, Li Y, Chopp M. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma. 2007b;24(7):1132–1146. [PubMed: 17610353] Mahmood A, Goussev A, Kazmi H, Qu C, Lu D, Chopp M. Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurgery. 2009; 65(1):187–191. [PubMed:19574841] Mahmood A, Lu D, Chopp M. Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma. 2004a;21(1):33–39. [PubMed: 14987463] Mahmood A, Lu D, Chopp M. Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery. 2004b; 55(5):1185–1193.
[PubMed: 15509325] Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery. 2005; 57(5):1026–1031.
discussion 1026–1031. [PubMed: 16284572] Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats. J Neurosurg. 2006; 104(2):272–277. [PubMed: Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats. Neurosurgery. 2007a; 60(3):546–553. [PubMed: 17327800] Mahmood A, Lu D, Qu C, Goussev A, Zhang ZG, Lu C, Chopp M. Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg. 2007b; 107(2):392–397. [PubMed: 17695395] Mammis A, Mcintosh TK, Maniker AH. Erythropoietin as a neuroprotective agent in traumatic brain injury Review. Surg Neurol. 2009; 71(5):527–531. discussion 531. [PubMed: 18789503] Morgan R, Kreipke CW, Roberts G, Bagchi M, Rafols JA. Neovascularization following traumatic brain injury: possible evidence for both angiogenesis and vasculogenesis. Neurol Res. 2007; 29(4):375–381. [PubMed: 17626733] Morris DC, Chopp M, Zhang L, Lu M, Zhang ZG. Thymosin beta4 improves functional neurological outcome in a rat model of embolic stroke. Neuroscience. 2010a; 169(2):674–682. [PubMed:20627173] Morris DC, Chopp M, Zhang L, Zhang ZG. Thymosin beta4: a candidate for treatment of stroke? Ann N Y Acad Sci. 2010b; 1194:112–117. [PubMed: 20536457] Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, Bullock MR, Choi SC, Clifton GL, Contant CF, Coplin WM, Dietrich WD, Ghajar J, Grady SM, Grossman RG, Hall ED,Heetderks W, Hovda DA, Jallo J, Katz RL, et al. Clinical trials in head injury. J Neurotrauma.
2002; 19(5):503–557. [PubMed: 12042091] Oshima T, Lee S, Sato A, Oda S, Hirasawa H, Yamashita T. TNF-alpha contributes to axonal sprouting and functional recovery following traumatic brain injury. Brain Res. 2009; 1290:102–110. [PubMed: 19616519] Qu C, Mahmood A, Lu D, Goussev A, Xiong Y, Chopp M. Treatment of traumatic brain injury in mice with marrow stromal cells. Brain Res. 2008; 1208:234–239. [PubMed: 18384759] Richardson RM, Sun D, Bullock MR. Neurogenesis after traumatic brain injury. Neurosurg Clin N Am. 2007; 18(1):169–181. xi. [PubMed: 17244562] Scheff SW, Price DA, Hicks RR, Baldwin SA, Robinson S, Brackney C. Synaptogenesis in the hippocampal CA1 field following traumatic brain injury. J Neurotrauma. 2005; 22(7):719–732.
[PubMed: 16004576] Discov Med. Author manuscript; available in PMC 2011 November 1.
Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J CerebBlood Flow Metab. 2007; 27(1):6–13. [PubMed: 16596121] Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, Chien KR, Riley PR. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature. 2007; 445(7124):177–182. [PubMed: 17108969] Smith JM, Lunga P, Story D, Harris N, Le Belle J, James MF, Pickard JD, Fawcett JW. Inosine promotes recovery of skilled motor function in a model of focal brain injury. Brain. 2007; 130(Pt4):915–925. [PubMed: 17293357] Stoica B, Byrnes K, Faden AI. Multifunctional drug treatment in neurotrauma. Neurotherapeutics.
Sun D, Mcginn MJ, Zhou Z, Harvey HB, Bullock MR, Colello RJ. Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its associationto cognitive recovery. Exp Neurol. 2007; 204(1):264–272. [PubMed: 17198703] Sun W, Kim H. Neurotrophic roles of the beta-thymosins in the development and regeneration of the nervous system. Ann N Y Acad Sci. 2007; 1112:210–218. [PubMed: 17468233] Walker PA, Harting MT, Jimenez F, Shah SK, Pati S, Dash PK, Cox CS Jr. Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. Stem Cells Dev. 2010; 19(6):867–876. [PubMed:19775197] Wang L, Chopp M, Gregg SR, Zhang RL, Teng H, Jiang A, Feng Y, Zhang ZG. Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. J Cereb Blood FlowMetab. 2008; 28(7):1361–1368. [PubMed: 18414495] Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004; 35(7):1732–1737. [PubMed: 15178821] Wible EF, Laskowitz DT. Statins in traumatic brain injury. Neurotherapeutics. 2010; 7(1):62–73.
Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, Mahmood A, Zhou D, Chopp M. Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis bysimvastatin after traumatic brain injury. J Neurosurg. 2008a; 109(4):691–698. [PubMed:18826357] Wu H, Lu D, Jiang H, Xiong Y, Qu C, Li B, Mahmood A, Zhou D, Chopp M. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase ofneurogenesis are associated with therapeutic improvement after traumatic brain injury. JNeurotrauma. 2008b; 25(2):130–139. [PubMed: 18260796] Xiong Y, Lu D, Qu C, Goussev A, Schallert T, Mahmood A, Chopp M. Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. JNeurosurg. 2008; 109(3):510–521. [PubMed: 18759585] Xiong Y, Mahmood A, Meng Y, Zhang Y, Qu C, Schallert T, Chopp M. Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, andimproving functional outcome following traumatic brain injury in rats: comparison of treatmentwith single and triple dose. J Neurosurg. 2010a; 113(3):598–608. [PubMed: 19817538] Xiong Y, Mahmood A, Meng Y, Zhang Y, Zhang ZG, Morris DC, Chopp M. Treatment of traumatic brain injury with thymosin beta(4) in rats. J Neurosurg. 2010b in press.
Xiong Y, Qu C, Mahmood A, Liu Z, Ning R, Li Y, Kaplan DL, Schallert T, Chopp M. Delayed transplantation of human marrow stromal cell-seeded scaffolds increases transcallosal neural fiberlength, angiogenesis, and hippocampal neuronal survival and improves functional outcome aftertraumatic brain injury in rats. Brain Res. 2009; 1263:183–191. [PubMed: 19368838] Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell. 2007; 1(1):39–49. [PubMed: 18371333] Yang XT, Bi YY, Feng DF. From the vascular microenvironment to neurogenesis. Brain Res Bull.
Discov Med. Author manuscript; available in PMC 2011 November 1.
Yoshimura S, Teramoto T, Whalen MJ, Irizarry MC, Takagi Y, Qiu J, Harada J, Waeber C, Breakefield XO, Moskowitz MA. FGF-2 regulates neurogenesis and degeneration in the dentategyrus after traumatic brain injury in mice. J Clin Invest. 2003; 112(8):1202–1210. [PubMed: Zhang J, Zhang ZG, Morris D, Li Y, Roberts C, Elias SB, Chopp M. Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis. Neuroscience.
2009a; 164(4):1887–1893. [PubMed: 19782721] Zhang Y, Xiong Y, Mahmood A, Meng Y, Liu Z, Qu C, Chopp M. Sprouting of corticospinal tract axons from the contralateral hemisphere into the denervated side of the spinal cord is associatedwith functional recovery in adult rat after traumatic brain injury and erythropoietin treatment.
Brain Res. 2010; 1353:249–257. [PubMed: 20654589] Zhang Y, Xiong Y, Mahmood A, Meng Y, Qu C, Schallert T, Chopp M. Therapeutic effects of erythropoietin on histological and functional outcomes following traumatic brain injury in rats areindependent of hematocrit. Brain Res. 2009b; 1294:153–164. [PubMed: 19646970] Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009; 8(5):491–500. [PubMed: 19375666] Zhang ZX, Guan LX, Zhang K, Zhang Q, Dai LJ. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy. 2008; 10(2):134–139. [PubMed: 18368592] Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell.
2008; 132(4):645–660. [PubMed: 18295581] Discov Med. Author manuscript; available in PMC 2011 November 1.
AZ44821C_Dzagnidze.qxd:AZ44821 Dzagnidze 1/12/08 17:05 Page 1 CHANGES IN ER BETA VERSUS ER ALPHA IN SHORT-TERM STUDIES OF ANTI-ESTROGEN THERAPIES Giorgi Dzagnidze,1 Andrew R Green,2 Valerie Speirs,3 Henry Zhang,2 Abeer M Shaaban,4 Sally Garnett,5 Ian O Ellis,2 John FR Robertson,6 Justin Lindemann5 1National Oncology Center, Tbilisi, Georgia; 2Division of Pathology, School of Molecular Medical