Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats.

OBJECTIVE This study investigated the effects of a combination therapy of marrow stromal cells (MSCs) and statins (atorvastatin) after traumatic brain injury in rats. METHODS Thirty-two female Wistar rats were injured by controlled cortical impact and divided into four groups. Group I was injected with MSCs (1 x 10(6)) intravenously 24 hrs after traumatic brain injury. Group II was administered atorvastatin (0.5 mg/kg) orally for 14 days starting 24 hours after traumatic brain injury. Group III received MSCs (1 x 10(6)) combined with atorvastatin (0.5 mg/kg). Group IV (control) was injected with saline. MSCs were harvested from the bone marrow of male rats to identify male donor cells within female recipient animals by localization of Y chromosomes. Functional analysis was performed using modified neurological severity scores and the Morris water maze test. Animals were sacrificed 35 days after injury and brain sections stained with immunohistochemistry. RESULTS No functional improvement was seen in animals treated with MSCs or atorvastatin alone (Groups I and II). However, functional improvement was seen with both testing modalities (modified neurological severity scores and Morris water maze) in animals receiving combination therapy (Group III). Microscopic analysis showed that significantly more MSCs were present in animals receiving combination therapy than in those receiving MSCs alone. Also, significantly more endogenous cellular proliferation was seen in the hippocampus and injury boundary zone of the combination therapy group than in the monotherapy or control groups. CONCLUSION When administered in combination with MSCs, atorvastatin increases MSC access and/or survival within the injured brain and enhances functional recovery compared with monotherapy.

[1]  M. Chopp,et al.  Human Marrow Stromal Cell Treatment Provides Long-lasting Benefit after Traumatic Brain Injury in Rats , 2005, Neurosurgery.

[2]  M. Chopp,et al.  Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  M. Chopp,et al.  Delayed thrombosis after traumatic brain injury in rats. , 2004, Journal of neurotrauma.

[4]  Michael Chopp,et al.  Marrow Stromal Cell Transplantation after Traumatic Brain Injury Promotes Cellular Proliferation within the Brain , 2004, Neurosurgery.

[5]  M. Chopp,et al.  Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury. , 2004, Journal of neurosurgery.

[6]  M. Chopp,et al.  Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. , 2004, Journal of neurotrauma.

[7]  M. Chopp,et al.  Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. , 2004, Journal of neurotrauma.

[8]  M. Chopp,et al.  Biologic Transplantation and Neurotrophin‐Induced Neuroplasticity After Traumatic Brain Injury , 2003, The Journal of head trauma rehabilitation.

[9]  M. Chopp,et al.  Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. , 2002, Journal of neurotrauma.

[10]  M. Chopp,et al.  Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery , 2002, Neurology.

[11]  Sean M. Grady,et al.  Clinical trials in head injury. , 2002, Neurological research.

[12]  M. Chopp,et al.  Treatment of Traumatic Brain Injury in Female Rats with Intravenous Administration of Bone Marrow Stromal Cells , 2001 .

[13]  M. Chopp,et al.  Treatment of Traumatic Brain Injury in Adult Rats with Intravenous Administration of Human Bone Marrow Stromal Cells , 2001, Neurosurgery.

[14]  M. Chopp,et al.  Intraarterial administration of marrow stromal cells in a rat model of traumatic brain injury. , 2001, Journal of neurotrauma.

[15]  Masahiro Yamaguchi,et al.  Generation of Dopaminergic Neurons in the Adult Brain from Mesencephalic Precursor Cells Labeled with a nestin-GFP Transgene , 2001, The Journal of Neuroscience.

[16]  M. Chopp,et al.  Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome , 2001, Neuroreport.

[17]  Y. Barde,et al.  Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. , 2000, Genes & development.

[18]  T. Palmer,et al.  Vascular niche for adult hippocampal neurogenesis , 2000, The Journal of comparative neurology.

[19]  E. Parati,et al.  Isolation and intracerebral grafting of nontransformed multipotential embryonic human CNS stem cells. , 1999, Journal of neurotrauma.

[20]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[21]  S. Rafii,et al.  Endothelial Trophic Support of Neuronal Production and Recruitment from the Adult Mammalian Subependyma , 1999, Molecular and Cellular Neuroscience.

[22]  M. Hatten,et al.  Generation of cerebellar granule neurons in vivo by transplantation of BMP-treated neural progenitor cells , 1999, Nature Neuroscience.

[23]  W. Silverman,et al.  Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures , 1999, Neuroscience.

[24]  J. Trojanowski,et al.  Improvement of cognitive deficits and decreased cholinergic neuronal cell loss and apoptotic cell death following neurotrophin infusion after experimental traumatic brain injury. , 1997, Journal of neurosurgery.

[25]  R. Hayes,et al.  Nerve Growth Factor Attenuates Cholinergic Deficits Following Traumatic Brain Injury in Rats , 1997, Experimental Neurology.

[26]  É. Mezey,et al.  Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  G. Clifton,et al.  A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat , 1997, Neuroscience.

[28]  S. Wiegand,et al.  BDNF Enhances the Functional Reinnervation of the Striatum by Grafted Fetal Dopamine Neurons , 1996, Experimental Neurology.

[29]  T. Mcintosh,et al.  Nerve Growth Factor Administration Attenuates Cognitive but Not Neurobehavioral Motor Dysfunction or Hippocampal Cell Loss Following Fluid‐Percussion Brain Injury in Rats , 1995, Journal of neurochemistry.

[30]  E. Shohami,et al.  Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat , 1995, Brain Research.

[31]  Ronald L. Hayes,et al.  A controlled cortical impact model of traumatic brain injury in the rat , 1991, Journal of Neuroscience Methods.

[32]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[33]  F. C. Lucibello,et al.  Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. , 2001, European journal of cell biology.

[34]  C. D. DE GROOT,et al.  Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non‐radioactive in situ hybridization and immunoperoxidase techniques , 1992, Glia.