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1.
Neurotherapeutics ; 20(6): 1446-1456, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37639189

ABSTRACT

Traumatic brain injury (TBI), a neurovascular injury caused by external force, is a common diagnosis among veterans and those experiencing homelessness (HL). There is a significant overlap in the veteran and homeless population, possibly accounting for the two to seven times greater incidence of TBI among those experiencing HL than the general population. Despite these statistics, individuals experiencing HL are often underdiagnosed and ineffectively treated for TBI. We introduced a novel model of HL. Over 5 weeks, adult Sprague-Dawley rats were randomly assigned to one of the following conditions: TBI only, HL only, TBI + HL, or control (n = 9 per group). To emulate HL, animals (2 animals per cage) were exposed to soiled beddings for 5 weeks. Subsequently, animals were introduced to TBI by using the moderate controlled cortical impact model, then underwent 4 consecutive days of behavioral testing (beam walk (BW), elevated body swing test (EBST), forelimb akinesia (FA), paw grasp (PG), Rotorod, and elevated T-maze). Nissl staining was performed to determine the peri-impact cell survival and the integrity of corpus callosum area. Motor function was significantly impaired by TBI, regardless of housing (beam walk or BW 85.0%, forelimb akinesia or FA 104.7%, and paw grasp or PG 100% greater deficit compared to control). Deficits were worsened by HL in TBI rats (BW 93.3%, FA 40.5%, and PG 50% greater deficit). Two-way ANOVA revealed BW (F(4, 160) = 31.69, p < 0.0001), FA (F(4, 160) = 13.71, p < 0.0001), PG (F(4, 160) = 3.873, p = 0.005), Rotorod (F(4, 160), p = 1.116), and EBST (F(4, 160) = 6.929, p < 0.0001) showed significant differences between groups. The Rotorod and EBST tests showed TBI-induced functional deficits when analyzed by day, but these deficits were not exacerbated by HL. TBI only and TBI + HL rats exhibited typical cortical impact damage (F(3,95) = 51.75, p < 0.0001) and peri-impact cell loss compared to control group (F(3,238) = 47.34, p < 0.0001). Most notably, TBI + HL rats showed significant alterations in WM area measured via the corpus callosum (F(3, 95) = 3.764, p = 0.0133). Worsened behavioral outcomes displayed by TBI + HL rats compared to TBI alone suggest HL contributes to TBI functional deficits. While an intact white matter, such as the corpus callosum, may lessen the consequent functional deficits associated with TBI by enhancing hemispheric communications, there are likely alternative cellular and molecular pathways mitigating TBI-associated inflammatory or oxidative stress responses. Here, we showed that the environmental condition of the patient, i.e., HL, participates in white matter integrity and behavioral outcomes, suggesting its key role in the disease diagnosis to aptly treat TBI patients.


Subject(s)
Brain Injuries, Traumatic , Ill-Housed Persons , White Matter , Humans , Adult , Rats , Animals , Rats, Sprague-Dawley , Brain Injuries, Traumatic/therapy , Comorbidity
2.
Stem Cells Int ; 2022: 2454168, 2022.
Article in English | MEDLINE | ID: mdl-35035489

ABSTRACT

Chondropathies are increasing worldwide, but effective treatments are currently lacking. Mesenchymal stromal cell (MSCs) transplantation represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA) and rheumatoid arthritis (RA). Umbilical cord- (UC-) MSCs gained increasing interest due to their multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties as well as higher proliferation rates, abundant supply along with no risks for the donor compared to adult MSCs. In addition, UC-MSCs are physiologically adapted to survive in an ischemic and nutrient-poor environment as well as to produce an extracellular matrix (ECM) similar to that of the cartilage. All these characteristics make UC-MSCs a pivotal source for a stem cell-based treatment of chondropathies. In this review, the regenerative potential of UC-MSCs for the treatment of cartilage diseases will be discussed focusing on in vitro, in vivo, and clinical studies.

3.
Prog Neurobiol ; 163-164: 79-97, 2018.
Article in English | MEDLINE | ID: mdl-28414101

ABSTRACT

Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.


Subject(s)
Autophagy/physiology , Cerebral Hemorrhage/physiopathology , Stroke/physiopathology , Animals , Autophagy/drug effects , Cerebral Hemorrhage/drug therapy , Humans , Stroke/drug therapy
4.
Minerva Med ; 106(3): 169-75, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25000217

ABSTRACT

Delivery of melatonin and targeting melatonin receptors pose as neuroprotective strategies for stroke therapy. The potential of melatonin-based therapeutics for clinical application in stroke patients requires translational research to guide the conduct of clinical trials. We review recent preclinical and clinical data that support the use of melatonin for stroke.


Subject(s)
Melatonin/therapeutic use , Stroke/drug therapy , Clinical Trials as Topic , Humans , Receptors, Melatonin/drug effects
5.
J Neurosurg Sci ; 58(3): 145-9, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24844175

ABSTRACT

Traumatic brain injury (TBI), often called the signature wound of Iraq and Afghanistan wars, is characterized by a progressive histopathology and long-lasting behavioral deficits. Treatment options for TBI are limited and patients are usually relegated to rehabilitation therapy and a handful of experimental treatments. Stem cell-based therapies offer alternative treatment regimens for TBI, and have been intended to target the delayed therapeutic window post-TBI, in order to promote "neuroregeneration," in lieu of "neuroprotection" which can be accomplished during acute TBI phase. However, these interventions may require adjunctive pharmacological treatments especially when aging is considered as a comorbidity factor for post-TBI health outcomes. Here, we put forward the concept that a combination therapy of human umbilical cord blood cell (hUCB) and granulocyte-colony stimulating factor (G-CSF) attenuates neuroinflammation in TBI, in view of the safety and efficacy profiles of hUCB and G-CSF, their respective mechanisms of action, and efficacy of hUCB+G-CSF combination therapy in TBI animal models. Further investigations on the neuroinflammatory pathway as a key pathological hallmark in acute and chronic TBI and also as a major therapeutic target of hUCB+G-CSF are warranted in order to optimize the translation of this combination therapy in the clinic.


Subject(s)
Aging/physiology , Brain Injuries/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Inflammation/drug therapy , Stem Cells , Animals , Comorbidity , Humans , Inflammation/epidemiology
6.
Leukemia ; 25(11): 1674-86, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21727900

ABSTRACT

Mobilizing bone cells to the head, astutely referred to as 'bonehead' therapeutic approach, represents a major discipline of regenerative medicine. The last decade has witnessed mounting evidence supporting the capacity of bone marrow (BM)-derived cells to mobilize from BM to peripheral blood (PB), eventually finding their way to the injured brain. This homing action is exemplified in BM stem cell mobilization following ischemic brain injury. Here, I review accumulating laboratory studies implicating the role of therapeutic mobilization of transplanted BM stem cells for brain plasticity and remodeling in stroke.


Subject(s)
Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/pathology , Stroke/surgery , Humans
7.
Placenta ; 32 Suppl 4: S285-90, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21575989

ABSTRACT

The International Placenta Stem Cell Society (IPLASS) was founded in June 2010. Its goal is to serve as a network for advancing research and clinical applications of stem/progenitor cells isolated from human term placental tissues, including the amnio-chorionic fetal membranes and Wharton's jelly. The commitment of the Society to champion placenta as a stem cell source was realized with the inaugural meeting of IPLASS held in Brescia, Italy, in October 2010. Officially designated as an EMBO-endorsed scientific activity, international experts in the field gathered for a 3-day meeting, which commenced with "Meet with the experts" sessions, IPLASS member and board meetings, and welcome remarks by Dr. Ornella Parolini, President of IPLASS. The evening's highlight was a keynote plenary lecture by Dr. Diana Bianchi. The subsequent scientific program consisted of morning and afternoon oral and poster presentations, followed by social events. Both provided many opportunities for intellectual exchange among the 120 multi-national participants. This allowed a methodical and deliberate evaluation of the status of placental cells in research in regenerative and reparative medicine. The meeting concluded with Dr. Parolini summarizing the meeting's highlights. This further prepared the fertile ground on which to build the promising potential of placental cell research. The second IPLASS meeting will take place in September 2012 in Vienna, Austria. This meeting report summarizes the thought-provoking lectures delivered at the first meeting of IPLASS.


Subject(s)
Fetal Stem Cells/cytology , Placenta/cytology , Female , Fetus , Humans , Pregnancy
8.
Placenta ; 32 Suppl 4: S320-5, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21570115

ABSTRACT

In addition to the placenta, umbilical cord and amniotic fluid, the amniotic membrane is emerging as an immensely valuable and easily accessible source of stem and progenitor cells. This concise review will focus on the stem/progenitor cell properties of human amniotic epithelial and mesenchymal stromal cells and evaluate the effects exerted by these cells and the amniotic membrane on tissue inflammation and fibrosis.


Subject(s)
Amnion/cytology , Mesenchymal Stem Cells/cytology , Stem Cell Transplantation/methods , Stem Cells/cytology , Animals , Cell Differentiation/physiology , Female , Fibrosis/surgery , Humans , Pregnancy
9.
Neuroscience ; 171(4): 1273-82, 2010 Dec 29.
Article in English | MEDLINE | ID: mdl-20950674

ABSTRACT

Traumatic brain injury (TBI) causes massive brain damage. However, the secondary injury and temporal sequence of events with multiple mechanisms after the insult has not been elucidated. Here, we examined the occurrence of apoptosis and a causal relationship between inflammation and apoptosis in the TBI brain. Following a lateral moderate fluid percussion injury model of TBI in adult rats, microarray analyses detected apparent changes in the expression levels of apoptosis-related genes which revealed time-dependent expression patterns for 23 genes in the lateral cortex. The upregulated 23 genes included inflammatory cytokines such as interleukin 1 (IL-1) α, IL-1ß, and tumor necrotic factor (TNF) which immediately increased at 3 h following the injury. Time-dependent gene expression profile analyses showed that apoptosis was subsequently induced following inflammation. These results taken together suggested changes in expression of apoptosis-related genes may be associated with inflammatory response. Accompanying this surge of cell death genes after TBI was a neurostructural pathologic hallmark of apoptosis characterized by leakage of cytochrome c into cytoplasm, DNA fragmentation and apoptotic cells in the lateral cortex of the impacted hemisphere. Caspase-3 positive cells in the TBI brain were initially sporadic after 3 h, but these apoptotic cells subsequently increased and populated the cerebral cortex at 6 and 12 h, and gradually reached a plateau by 48 h. Interestingly, the expression profile of CD68 macrophage labeled cells closely resembled that of apoptotic cells after TBI, including the role of inflammatory signaling pathway in the progression of apoptotic cell death. These results taken together suggest that TBI induced upregulation of apoptosis-related genes, concomitant with the detection of apoptotic brain pathology during the 3-48 h post-injury period, which may be likely mediated by inflammation. Therapies designed at abrogating apoptosis and/or inflammation may prove effective when initiated at this subacute TBI phase.


Subject(s)
Brain Injuries/complications , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Encephalitis , Gene Expression Regulation/physiology , Percussion/adverse effects , Animals , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Apoptosis/genetics , Brain Injuries/etiology , Brain Injuries/pathology , Caspase 3/metabolism , Cerebral Cortex/physiopathology , Cytochromes c/metabolism , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Encephalitis/etiology , Encephalitis/genetics , Encephalitis/pathology , Gene Expression Profiling/methods , In Situ Nick-End Labeling/methods , Male , Oligonucleotide Array Sequence Analysis/methods , Phosphopyruvate Hydratase/metabolism , Rats , Rats, Wistar , Time Factors
10.
J Cell Mol Med ; 14(4): 914-21, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20569276

ABSTRACT

We recently demonstrated that blood-brain barrier permeabilization using mannitol enhances the therapeutic efficacy of systemically administered human umbilical cord blood (HUCB) by facilitating the entry of neurotrophic factors from the periphery into the adult stroke brain. Here, we examined whether the same blood-brain barrier manipulation approach increases the therapeutic effects of intravenously delivered HUCB in a neonatal hypoxic-ischaemic (HI) injury model. Seven-day-old Sprague-Dawley rats were subjected to unilateral HI injury and then at day 7 after the insult, animals intravenously received vehicle alone, mannitol alone, HUCB cells (15k mononuclear fraction) alone or a combination of mannitol and HUCB cells. Behavioural tests at post-transplantation days 7 and 14 showed that HI animals that received HUCB cells alone or when combined with mannitol were significantly less impaired in motor asymmetry and motor coordination compared with those that received vehicle alone or mannitol alone. Brain tissues from a separate animal cohort from the four treatment conditions were processed for enzyme-linked immunosorbent assay at day 3 post-transplantation, and revealed elevated levels of GDNF, NGF and BDNF in those that received HUCB cells alone or when combined with mannitol compared with those that received vehicle or mannitol alone, with the combined HUCB cells and mannitol exhibiting the most robust neurotropic factor up-regulation. Histological assays revealed only sporadic detection of HUCB cells, suggesting that the trophic factor-mediated mechanism, rather than cell replacement per se, principally contributed to the behavioural improvement. These findings extend the utility of blood-brain barrier permeabilization in facilitating cell therapy for treating neonatal HI injury.


Subject(s)
Behavior, Animal/drug effects , Cord Blood Stem Cell Transplantation , Hypoxia-Ischemia, Brain/pathology , Hypoxia-Ischemia, Brain/therapy , Mannitol/pharmacology , Nerve Growth Factors/genetics , Up-Regulation/drug effects , Animals , Animals, Newborn , Brain/drug effects , Brain/pathology , Cell Survival/drug effects , Dendrites/drug effects , Dendrites/pathology , Graft Survival/drug effects , Hippocampus/drug effects , Hippocampus/pathology , Humans , Hypoxia-Ischemia, Brain/metabolism , Nerve Growth Factors/metabolism , Rats , Rats, Sprague-Dawley
11.
Cell Prolif ; 41 Suppl 1: 94-114, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18181951

ABSTRACT

Cells of the central nervous system were once thought to be incapable of regeneration. This dogma has been challenged in the last decade with studies showing new, migrating stem cells in the brain in many rodent injury models and findings of new neurones in the human hippocampus in adults. Moreover, there are reports of bone marrow-derived cells developing neuronal and vascular phenotypes and aiding in repair of injured brain. These findings have fuelled excitement and interest in regenerative medicine for neurological diseases, arguably the most difficult diseases to treat. There are numerous proposed regenerative approaches to neurological diseases. These include cell therapy approaches in which cells are delivered intracerebrally or are infused by an intravenous or intra-arterial route; stem cell mobilization approaches in which endogenous stem and progenitor cells are mobilized by cytokines such as granulocyte colony stimulatory factor (GCSF) or chemokines such as SDF-1; trophic and growth factor support, such as delivering brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) into the brain to support injured neurones; these approaches may be used together to maximize recovery. While initially, it was thought that cell therapy might work by a 'cell replacement' mechanism, a large body of evidence is emerging that cell therapy works by providing trophic or 'chaperone' support to the injured tissue and brain. Angiogenesis and neurogenesis are coupled in the brain. Increasing angiogenesis with adult stem cell approaches in rodent models of stroke leads to preservation of neurones and improved functional outcome. A number of stem and progenitor cell types has been proposed as therapy for neurological disease ranging from neural stem cells to bone marrow derived stem cells to embryonic stem cells. Any cell therapy approach to neurological disease will have to be scalable and easily commercialized if it will have the necessary impact on public health. Currently, bone marrow-derived cell populations such as the marrow stromal cell, multipotential progenitor cells, umbilical cord stem cells and neural stem cells meet these criteria the best. Of great clinical significance, initial evidence suggests these cell types may be delivered by an allogeneic approach, so strict tissue matching may not be necessary. The most immediate impact on patients will be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.


Subject(s)
Central Nervous System Diseases/therapy , Stem Cell Transplantation/methods , Stem Cells/cytology , Adult Stem Cells/cytology , Bone Marrow Transplantation , Brain/pathology , Cell Differentiation , Central Nervous System Diseases/pathology , Humans , Metabolism, Inborn Errors/pathology , Metabolism, Inborn Errors/therapy , Multiple Sclerosis/pathology , Multiple Sclerosis/therapy , Parkinson Disease/pathology , Parkinson Disease/therapy , Stroke/pathology , Stroke/therapy
12.
Neuroscience ; 149(1): 182-91, 2007 Oct 12.
Article in English | MEDLINE | ID: mdl-17869433

ABSTRACT

Bedridden patients who receive good physical rehabilitation are able to exhibit clinical improvement. Accumulating evidence demonstrates that exercise increases endogenous neurogenesis and may even protect against central nervous system (CNS) disorders. Here, we explored the effects of lack of exercise on neurogenesis in rats by employing a routine hindlimb suspension (HS) model over a 2-week period, which consists of elevating their tails, thereby raising their hindlimbs above the ground and unloading the weights in these extremities. In addition, the effects of exercise and recovery time with normal caging after HS were also explored. BrdU (50 mg/kg, i.p.) was injected every 8 h over the last 4 days of each paradigm to label proliferative cells. Immunohistochemical results revealed that HS significantly reduced the number of BrdU/Doublecortin double-positive cells in the subventricular zone and dentate gyrus. Exercise and recovery time significantly improved atrophy of the soleus muscle, but did not attenuate the HS-induced decrement in BrdU/Dcx-positive cells. A separate cohort of animals was exposed to the same HS paradigm and enzyme-linked immunosorbent assay (ELISA) of neurotrophic factors was performed on brain tissue samples harvested at the end of the HS period, as well as plasma samples from all animals. ELISA results revealed that HS reduced the levels of brain-derived neurotrophic factor in the hippocampus and vascular endothelial growth factor plasma levels. This study revealed that lack of exercise reduced neurogenesis with downregulation of neurotrophic factors. The use of the HS model in conjunction with CNS disease models should further elucidate the role of exercise in neurogenesis and neurotrophic factors in neurologic disorders.


Subject(s)
Brain/cytology , Cell Differentiation/physiology , Hindlimb Suspension , Neurons/physiology , Physical Conditioning, Animal/methods , Analysis of Variance , Animals , Behavior, Animal , Brain/metabolism , Bromodeoxyuridine/metabolism , Cell Count/methods , Corticosterone/metabolism , Doublecortin Domain Proteins , Doublecortin Protein , Down-Regulation/physiology , Enzyme-Linked Immunosorbent Assay/methods , Male , Microtubule-Associated Proteins/metabolism , Models, Animal , Motor Activity/physiology , Nerve Growth Factors/metabolism , Neuropeptides/metabolism , Rats , Rats, Wistar
13.
Brain Res ; 1160: 113-23, 2007 Jul 30.
Article in English | MEDLINE | ID: mdl-17573046

ABSTRACT

Ropinirole, which is a non-ergot dopamine agonist derivative, exerts therapeutic benefits in Parkinson's disease (PD). Based on recent studies implicating dopamine receptors 2 and 3 (D2R and D3R) as possible targets of ropinirole, we over-expressed these dopamine receptor genes in the dopamine-denervated striatum of rodents to reveal whether their over-expression modulated ropinirole activity. Adult Sprague-Dawley rats initially received unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. At 1 month after surgery, successfully lesioned animals (3 or less forelimb akinesia score, and 8 or more apomorphine-induced rotations/min over 1 h) were randomly assigned to intrastriatal injection (ipsilateral to the lesion) of blank lentiviral vector, D2R, D3R or both genes. At about 5 months post-lesion, ropinirole (0.2 mg/kg, i.p.) was administered daily for 9 consecutive days. The subtherapeutic dose of ropinirole improved the use of previously akinetic forelimb and produced robust circling behavior in lesioned animals with striatal over-expression of both D2R and D3R compared to lesioned animals that received blank vector. In contrast, the subtherapeutic dose of ropinirole generated only modest motor effects in lesioned animals with sole over-expression of D2R or D3R. Western immunoblot and autoradiographic assays showed enhanced D2R and D3R protein levels coupled with normalized D2R and D3R binding in the ventral striatum of lesioned animals with lentiviral over-expression of both D2R and D3R relative to vehicle-treated lesioned animals. Immunohistochemical analyses showed that D2R and D3R GFP fluorescent cells colocalized with enkephalin and substance P immunoreactive medium spiny neurons. These data support the use of the subtherapeutic dose of ropinirole in a chronic model of PD.


Subject(s)
Antiparkinson Agents/therapeutic use , Gene Expression Regulation/genetics , Indoles/therapeutic use , Parkinson Disease/drug therapy , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Adrenergic Agents/adverse effects , Animals , Animals, Genetically Modified , Behavior, Animal/drug effects , Disease Models, Animal , Forelimb/drug effects , Forelimb/physiopathology , Gene Transfer Techniques , Genetic Vectors/physiology , Lentivirus/physiology , Male , Medial Forebrain Bundle/drug effects , Motor Activity/drug effects , Motor Activity/physiology , Oxidopamine/adverse effects , Parkinson Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Protein Binding/drug effects , Protein Binding/genetics , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/genetics , Receptors, Dopamine D3/genetics
15.
Neuroreport ; 15(10): 1543-7, 2004 Jul 19.
Article in English | MEDLINE | ID: mdl-15232280

ABSTRACT

The present study examined the neuroprotective effects of choroid plexus isolated from adult rats and encapsulated within alginate microcapsules. In vitro, conditioned media from cultured choroid plexus produced a marked, dose-dependent protection of embryonic cortical neurons against serum deprivation-induced cell death. In vivo studies demonstrated that a one-hour middle cerebral artery occlusion in adult Wistar rats produced profound motor and neurological impairments 1-3 days after stroke. In contrast, stroke animals transplanted with encapsulated choroid plexus cells displayed a significant reduction in both motor and neurological abnormalities. Histological analysis 3 days post-transplantation revealed that choroid plexus transplants significantly decreased the volume of striatal infarction. This is the first report demonstrating the therapeutic potential of transplanted choroid plexus for stroke.


Subject(s)
Brain Ischemia/prevention & control , Brain Tissue Transplantation/methods , Choroid Plexus/cytology , Choroid Plexus/physiology , Neurons/transplantation , Analysis of Variance , Animals , Behavior , Brain Ischemia/pathology , Capsules/therapeutic use , Cell Death/drug effects , Cell Survival/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Infarction/pathology , Cerebral Infarction/surgery , Culture Media, Conditioned/pharmacology , Dose-Response Relationship, Drug , Embryo, Mammalian , Graft Survival/physiology , Locomotion/physiology , Male , Motor Activity/physiology , Neurons/drug effects , Rats , Rats, Wistar , Tetrazolium Salts , Time Factors
16.
Cell Transplant ; 13(3): 283-94, 2004.
Article in English | MEDLINE | ID: mdl-15191166

ABSTRACT

The present study characterized survival and immunologic response of bone marrow stromal cells (BMSCs) following transplantation into intact and stroke brains. In the first study, intrastriatal transplantation of BMSC (60,000 in 3 microl) or vehicle was performed in normal adult Sprague-Dawley male rats that subsequently received daily cyclosporin A (CsA, 10 mg/kg, IP in 3 ml) or vehicle (olive oil, similar volume) starting on day of surgery up to 3 days posttransplantation. Animals were euthanized at 3 or 30 days posttransplantation and brains were processed either for green fluorescent protein (GFP) microscopy or flow cytometry (FACS). Both GFP epifluorescence and FACS scanning revealed GFP+ BMSCs in both groups of transplanted rats with or without CsA, although significantly increased (1.6- to 3-fold more) survival of GFP+ BMSCs was observed in the immunosuppressed animals. Further histologic examination revealed widespread dispersal of BMSCs away from the graft core accompanied by many long outgrowth processes in non-CsA-transplanted animals, whereas a very dense graft core, with cells expressing only sporadic short outgrowth processes, was observed in CsA-transplanted animals. There were no detectable GFP+ BMSCs in nontransplanted rats that received CsA or vehicle. Immunologic response via FACS analysis revealed a decreased presence of cytotoxic cells, characterized by near complete absence of CD8+ cells, and lack of activation depicted by low CD69 expression in CsA-treated transplanted animals. In contrast, elevated levels of CD8+ cells and increased activation of CD69 expression were observed in transplanted animals that received vehicle alone. CD4+ helper cells were almost nondetectable in transplanted rats that received CsA, but also only minimally elevated in transplanted rats that received vehicle. Nontransplanted rats that received either CsA or vehicle displayed very minimal detectable levels of all three lymphocyte markers. In the second study, a new set of male Sprague-Dawley rats initially received bilateral stereotaxic intrastriatal transplantation of BMSCs and 3 days after were subjected to unilateral transient occlusion of middle cerebral artery. The animals were allowed to survive for 3 days after stroke without CsA immunosuppression. Epifluorescence microscopy revealed significantly higher (5-fold more) survival of transplanted GFP+ BMSCs in the stroke striatum compared with the intact striatum. The majority of the grafts remained within the original dorsal striatal transplant site, characterized by no obvious migration in intact striatum, but with long-distance migration along the ischemic penumbra in the stroke striatum. Moreover, FACS scanning analyses revealed low levels of immunologic response of grafted BMSCs in both stroke and intact striata. These results, taken together, suggest that xenotransplantation of mouse BMSCs into adult rats is feasible. Immunosuppression therapy can enhance xenograft survival and reduce graft-induced immunologic response; however, in the acute phase posttransplantation, BMSCs can survive in intact and stroke brain, and may even exhibit long-distance migration and increased outgrowth processes without immunosuppression.


Subject(s)
Bone Marrow Cells/cytology , Bone Marrow Transplantation/methods , Cell Transplantation/methods , Stroke/therapy , Transplantation, Heterologous/methods , Animals , Antigens, CD/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Bone Marrow Cells/metabolism , Cell Movement , Cell Separation , Cell Survival , Cyclosporine/pharmacology , Flow Cytometry/methods , Green Fluorescent Proteins/metabolism , Immunosuppressive Agents/pharmacology , Lectins, C-Type , Lymphocytes/metabolism , Male , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Time Factors
17.
Cell Transplant ; 12(3): 225-34, 2003.
Article in English | MEDLINE | ID: mdl-12797377

ABSTRACT

Chronic systemic melatonin treatment attenuates abnormalities produced by occlusion of middle cerebral artery (MCA) in adult rats. Because the pineal gland secretes high levels of melatonin, we examined in the present study whether transplantation of pineal gland exerted similar protective effects in MCA-occluded adult rats. Animals underwent same-day MCA occlusion and either intrastriatal transplantation of pineal gland (harvested from 2-month-old rats) or vehicle infusion. Behavioral tests (from day of surgery to 3 days posttransplantation) revealed that transplanted stroke rats displayed significantly less motor asymmetrical behaviors than vehicle-infused stroke rats. Histological analysis at 3 days posttransplantation revealed that transplanted stroke rats had significantly smaller cerebral infarction than vehicle-infused rats. Additional experiments showed that pinealectomy affected transplantation outcome, in that transplantation of pineal gland only protected against stroke-induced deficits in stroke animals with intact pineal gland, but not in pinealectomized stroke rats. Interestingly, nonpinealectomized vehicle-infused stroke rats, as well as pinealectomized transplanted stroke rats, had significantly lower melatonin levels in the cerebrospinal fluid than nonpinealectomized transplanted stroke rats. We conclude that intracerebral transplantation of pineal gland, in the presence of host intact pineal gland, protected against stroke, possibly through secretion of melatonin.


Subject(s)
Cell Transplantation , Melatonin/metabolism , Neurons/metabolism , Pineal Gland/metabolism , Stroke/therapy , Animals , Behavior, Animal , Cerebrovascular Circulation , Infarction, Middle Cerebral Artery , Male , Neurons/cytology , Pineal Gland/surgery , Rats , Rats, Sprague-Dawley , Regional Blood Flow
18.
Brain Res Bull ; 60(3): 297-306, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12754091

ABSTRACT

One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B(2) bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.


Subject(s)
Blood-Brain Barrier/physiology , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Capillary Permeability/physiology , Receptors, Bradykinin/physiology , Animals , Blood-Brain Barrier/drug effects , Bradykinin/therapeutic use , Capillary Permeability/drug effects , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/physiology , Drug Combinations , Drug Delivery Systems , Humans , Receptors, Bradykinin/drug effects
19.
Neurobiol Dis ; 8(4): 636-46, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11493028

ABSTRACT

Exogenous application of transforming growth factors-beta (TGF beta) family proteins, including glial cell line-derived neurotrophic factor (GDNF), neurturin, activin, and bone morphogenetic proteins, has been shown to protect neurons in many models of neurological disorders. Finding a tissue source containing a variety of these proteins may promote optimal beneficial effects for treatment of neurodegenerative diseases. Because fetal kidneys express many TGF beta trophic factors, we transplanted these tissues directly into the substantia nigra after a unilateral 6-hydroxydopamine lesion. We found that animals that received fetal kidney tissue grafts exhibited (1) significantly reduced hemiparkinsonian asymmetrical behaviors, (2) a near normal tyrosine hydroxylase immunoreactivity in the lesioned nigra and striatum, (3) a preservation of K(+)-induced dopamine release in the lesioned striatum, and (4) high levels of GDNF protein within the grafts. In contrast, lesioned animals that received grafts of adult kidney tissues displayed significant behavioral deficits, dopaminergic depletion, reduced K(+)-mediated striatal dopamine release, and low levels of GDNF protein within the grafts. The present study suggests that fetal kidney tissue grafts can protect the nigrostriatal dopaminergic system against a neurotoxin-induced parkinsonism, possibly through the synergistic release of GDNF and several other neurotrophic factors.


Subject(s)
Fetal Tissue Transplantation , Kidney Transplantation , Nerve Growth Factors , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neuroprotective Agents/metabolism , Parkinsonian Disorders/surgery , Age Factors , Animals , Behavior, Animal , Corpus Striatum/metabolism , Dopamine/metabolism , Enzyme-Linked Immunosorbent Assay , Glial Cell Line-Derived Neurotrophic Factor , Kidney/cytology , Kidney/metabolism , Male , Nerve Tissue Proteins/analysis , Neurons/drug effects , Neurons/enzymology , Neuroprotective Agents/analysis , Oxidopamine , Parkinsonian Disorders/pathology , Rats , Rats, Sprague-Dawley , Substantia Nigra/cytology , Substantia Nigra/surgery , Sympatholytics , Transplants , Tyrosine 3-Monooxygenase/metabolism
20.
Brain Res ; 904(1): 67-75, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11516412

ABSTRACT

Previous reports have demonstrated that exogeneous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ventral mesencephalic (VM) dopaminergic (DA) neuron damage induced by 6-hydroxydopamine (6-OHDA) lesioning in rats. Recent studies have shown that 1,25-dihydroxyvitamin D(3) (D3) enhances endogenous GDNF expression in vitro and in vivo. The purpose of present study was to investigate if administration of D3 in vivo and in vitro would protect against 6-OHDA-induced DA neuron injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for 8 days and then lesioned unilaterally with 6-OHDA into the medial forebrain bundle. Locomotor activity was measured using automated activity chambers. We found that unilateral 6-OHDA lesioning reduced locomotor activity in saline-pretreated animals. Pretreatment with D3 for 8 days significantly restored locomotor activity in the lesioned animals. All animals were sacrificed for neurochemical analysis 6 weeks after lesioning. We found that 6-OHDA administration significantly reduced dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanilic acid (HVA) levels in the substantia nigra (SN) on the lesioned side in the saline-treated rats. D3 pretreatment protected against 6-OHDA-mediated depletion of DA and its metabolites in SN. Using primary cultures obtained from the VM of rat embryos, we found that 6-OHDA or H(2)O(2) alone caused significant cell death. Pretreatment with D3 (10(-10) M) protected VM neurons against 6-OHDA- or H(2)O(2)-induced cell death in vitro. Taken together, our data indicate that D3 pretreatment attenuates the hypokinesia and DA neuronal toxicity induced by 6-OHDA. Since both H(2)O(2) and 6-OHDA may injure cells via free radical and reactive oxygen species, the neuroprotection seen here may operate via a reversal of such a toxic mechanism.


Subject(s)
Cholecalciferol/pharmacology , Drug Interactions/physiology , Mesencephalon/drug effects , Nerve Degeneration/drug therapy , Nerve Growth Factors , Neuroprotective Agents/pharmacology , Neurotoxins/antagonists & inhibitors , Oxidopamine/pharmacology , Sympatholytics/pharmacology , Animals , Cells, Cultured , Dopamine/metabolism , Glial Cell Line-Derived Neurotrophic Factor , Immunohistochemistry , Male , Mesencephalon/pathology , Mesencephalon/physiopathology , Motor Activity/drug effects , Motor Activity/physiology , Nerve Degeneration/chemically induced , Nerve Degeneration/physiopathology , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/pathology , Neurotoxins/pharmacology , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Rats , Rats, Sprague-Dawley , Substantia Nigra/drug effects , Substantia Nigra/pathology , Substantia Nigra/physiopathology , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/pathology , Ventral Tegmental Area/physiopathology
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