Stem Cell Therapy in Brain Trauma: Implications for Repair and Regeneration of Injured Brain in Experimental TBI Models

Rolfe, Andrew; Sun, Dong

doi:10.1201/b18126-49

Cited by 30 publications

(33 citation statements)

References 90 publications

(103 reference statements)

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“…Neurogenesis has been observed in response to trauma and other insults, suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons (Rolfe and Sun, 2015). Therefore, therapeutic treatments and approaches with neurogenic capacity could be applicable therapies for treating patients with stroke and TBI.…”

Section: Discussionmentioning

confidence: 99%

DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

Zhao

Lee

Chen

et al. 2017

Neurochemistry International

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Previous investigations suggest that DL-3-n-butylphthalide (NBP) is a promising multifaceted drug for the treatment of stroke. It is not clear whether NBP can treat traumatic brain injury (TBI) and what could be the mechanisms of therapeutic benefits. To address these issues, TBI was induced by a controlled cortical impact in adult male mice. NBP (100 mg/kg) or saline was intraperitoneally administered within 5 min after TBI. One day after TBI, apoptotic events including caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) translocation into the nucleus in the pericontusion region were attenuated in NBP-treated mice compared to TBI-saline controls. In the assessment of the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway, NBP ameliorated the p65 expression and the p-IκB-α/Iκ3-α ratio, indicating reduced NF-κB activation. Consistently, NBP reduced the upregulation of proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and interleukin-1beta (IL-1β) after TBI. In sub-acute treatment experiments, NBP was intranasally delivered once daily for 3 days. At 3 days after TBI, this repeated NBP treatment significantly reduced the contusion volume and cell death in the pericontusion region. In chronic experiments up to 21 days after TBI, continues daily intranasal NBP treatment increased neurogenesis, angiogenesis, and arteriogenesis in the post-TBI brain, accompanied with upregulations of regenerative genes including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), endothelial-derived nitric oxide synthase (eNOS), and matrix metallopeptidase 9 (MMP-9). The NBP treatment significantly improved sensorimotor functional recovery and reduced post-TBP depressive behavior. These new findings demonstrate that NBP shows multiple therapeutic benefits after TBI.

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Section: Discussionmentioning

confidence: 99%

DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

Zhao

Lee

Chen

et al. 2017

Neurochemistry International

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“…injury [165,[169][170][171][172] and potentially in clinical settings [173,174]. However, previous studies show that only a small proportion of transplanted MSCs actually survive and few MSCs differentiate into neural cells in injured brain tissues.…”

Section: Neuroprotective and Neurorestorative Processes In The Traumamentioning

confidence: 99%

“…Many factors may affect adult neurogenesis, such as growth factors, exercise, enriched environment, or stress [161]. Studies have shown that TBI induces an upregulation of neurogenesis in varying types of TBI models [165]. In that sense, strategies such as supplementing varying types of trophic factors (i.e.…”

Section: Neuroprotective and Neurorestorative Processes In The Traumamentioning

confidence: 99%

“…In that sense, strategies such as supplementing varying types of trophic factors (i.e. BDNF, VEGF, S100β), manipulating transcriptional regulators, or other pharmacological approaches targeting different aspects of the endogenous neurogenic response have shown promising results improving functional recovery following experimental models of TBI [45,155,161,165]. The potential use of cellular therapies to prevent secondary neural injury and promote recovery of injured tissue in trauma is an area of emerging investigation.…”

Section: Neuroprotective and Neurorestorative Processes In The Traumamentioning

confidence: 99%

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Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Regner¹,

Meirelles²,

Simon³

2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of "traumatic penumbra," represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery.

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“…1,[23][24][25] Several preclinical studies have evaluated the efficacy of rodent neural precursor cells in TBI rodent models. 22,[26][27][28][29][30] The culturing NSCs in vitro started as an attempt to grow multipotent embryonic cortical tissue (the word neural stem cells was not yet coined) and successfully accomplished in 1989 at the University of Miami. 31 This work evolved when Martin Raff, a Canadian born Boston neurologist decided to move to England and chose to leave the United States (US) than fight in Vietnam War and to pursue immunology.…”

Section: Step 1 Cell Therapy Candidatementioning

confidence: 99%

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

Gajavelli¹

2016

JSRT

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26As of 2015, a total of 49 ALS patients have received NSI-566 cells. Both the cells and surgery were well tolerated and the ALS studies reported a 47% responder rate with decline in disease progression and improved grip strength. Stem cells inc., on the other hand lost a patent dispute to NSI and recently closed operations.J Stem Cell Res Ther. 2016;1(4):160-164. 160© 2016 Shyam. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially.One step at a time, stem cell therapy for traumatic brain injury needs two more breakthroughs Step 2 ImmunosuppressionTransplantation of the cells conferred benefits such as restoration of injured neuronal morphology 45 and cognitive function. 46 even without immunosuppression. Transient immunosuppression was shown to be sufficient to support engraftment and transplanted derived neurons were reportedly present 6 months post transplantation. 47 However, no data quantifying either engraftment or behavior modification were presented. Such studies were limited by cyclosporine mediated immunosuppression which resulted in persistence of barriers to engraftment and demonstration of effectiveness of the approach. 48-50The initial optimism was replaced by skepticism if the therapeutic potential of neural stem cells: greater in people's perception than in their brains. 51,52 The US Food and Drug Administration (FDA; Rockville, MD) guidelines on preclinical assessment of cell therapies in the publication "Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products".53,54 A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month posttransplantation. 1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26The successful preclinical ALS, SCI and stroke studies. 40,41,44,56 have employed a different immunosuppression technique that was pioneered by Hefferan et al. 40 This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone. The combination has been found to be superior to cyclosporine, a standard immunosuppressant between 1999-2012. Step 3 Mechanism of actionHowever, due to the lack of exact mechanism of action still precludes attempts to move neural stem cell therapy to the clinic. 26Paul Lu et al. 41 demonstrated the mechanism of regeneration in spinal cord injury models. 41 Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. The recovery was lost subsequent to re-transection of the spinal cord....

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Stem Cell Therapy in Brain Trauma: Implications for Repair and Regeneration of Injured Brain in Experimental TBI Models

Cited by 30 publications

References 90 publications

DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

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