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This literature review focuses on the underlying pathophysiology of TBI and PTSD symptoms, while also examining the plethora of stem cell treatment options to ameliorate these neuronal and functional changes. As more veterans return suffering from TBI and/or PTSD, it is vital that researchers discover novel therapies to mitigate the detrimental symptoms of both diagnoses. A variety of stem cell treatments have been studied and offer hopeful options for TBI and PTSD recovery.

Accumulating evidence shows alterations in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) in ALS patients and in animal models of disease, mainly by endothelial cell (EC) damage. Repair of the altered barrier in the CNS by replacement of ECs via cell transplantation may be a new therapeutic approach for ALS. Recently, we demonstrated positive effects towards BSCB repair by intravenous administration of unmodified human bone marrow CD34+ (hBM34+) cells at different doses into symptomatic ALS mice. However, particular benefits of these transplanted cells on microvascular integrity in symptomatic ALS mice are still unclear. The aim of the present study was to determine the structural and functional spinal cord capillary integrity in symptomatic ALS mice after intravenous administration of hBM34+ cells. The G93A mice at 13 weeks of age intravenously received one of three different cell doses (5 × 104, 5 × 105, or 1 × 106) and were euthanized at 17 weeks of age (4 weeks post-transplant). Control groups were media-treated and non-carrier mutant SOD1 gene mice. Capillary ultrastructural (electron microscopy), immunohistochemical (laminin and HuNu), and histological (myelin and capillary density) analyses were performed in the cervical and lumbar spinal cords. Capillary permeability in the spinal cords was determined by Evans Blue (EB) injection. Results showed significant restoration of ultrastructural capillary morphology, improvement of basement membrane integrity, enhancement of axonal myelin coherence, and stabilization of capillary density in the spinal cords primarily of ALS mice receiving the high dose of 1 × 106 cells. Moreover, substantial reduction of parenchymal EB levels was determined in these mice, confirming our previous results on capillary permeability. Additionally, transplanted cells were detected in blood smears of sacrificed late symptomatic mice by HuNu marker. Altogether, these results provide novel evidence that unmodified bone marrow hematopoietic stem cell treatment at optimal dose might be beneficial for structural and functional repair of the damaged BSCB in advanced stage of ALS, potentially resulting in delayed disease progression by increased motor neuron survival.

The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1 day and astrocytes at 7 days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

The efficacy of hyperbaric oxygen (HBO) therapy for treatment of stroke remains to be validated in the laboratory. We report here that adult rats subjected to occlusion of the middle cerebral artery and subsequently exposed to HBO (3 atm, 2 x 90 min at a 24-h intervals; animals terminated shortly after the second treatment) or hyperbaric pressure (HBP; 3 atm, 2 x 90 min at a 24-h interval; animals terminated shortly after the second treatment) immediately after the ischemia or after a 60-min delay generally displayed recovery from motor deficits at 2.5 and 24 h of reperfusion, as well as a reduction in cerebral infarction at 24 h of reperfusion compared to ischemic animals subjected to normal atmospheric pressure. While both HBO and HBP treatments promoted beneficial effects, HBO produced more consistent protection than HBP. Treatment with HBO immediately or 60 min after reperfusion equally produced significant attenuations of cerebral infarction and motor deficits. In contrast, protective effects of HBP treatment against ischemia were noted only when administered immediately after ischemia, which resulted in a significantly reduced infarction volume, but only produced a trend toward decreased behavioral deficits. The present results demonstrate that HBO and, to some extent, HBP reduced ischemic brain damage and behavioral dysfunctions.

In the present study, several doses of lithium chloride were tested for their ability to induce the expression of tyrosine hydroxylase (TH) in neurons derived from a human teratocarcinoma cell line (hNT) after 5 and 10 days in vitro (DIV). Following immunocytochemical staining for tyrosine hydroxylase, the percentage of TH-positive neurons was determined and morphometric analysis, including mean soma profile area and neuritic length, was performed. hNT neurons responded to lithium treatment in a dose-dependent manner. In 5 DIV, the most effective dose of lithium chloride (1.0 mM) increased the number of TH-positive neurons approximately sixfold. In addition, both TH-positive hNT neuron mean soma profile area and neurite length were significantly larger than controls by 60 and 70%, respectively. Moreover, even after withdrawal of lithium chloride on day 5, the number of TH-positive neurons in 10 DIV cultures remained significantly increased. These data suggest that hNT cells are indeed responsive to lithium exposure and may serve as a continual source of TH-expressing neurons in new therapeutic approaches to degenerative brain disease.

Possible biologic treatments for Parkinson's disease, a disorder caused by the deterioration of dopaminergic neurons bridging the nigrostriatal system, have recently focused on fetal cell transplantation. Because of ethical and tissue availability issues concerning fetal cell transplantation, alternative cell sources are being developed. The adrenal medulla has been used as a cell transplant source because of the capacity of the cells to provide catecholamines and to transform into a neuronal phenotype. However, adrenal tissue transplants have shown limited success, primarily because of their lack of long-term viability. Recently, seeding adrenal chromaffin cells on microcarrier beads has been shown to enhance the cell viability following neural transplantation. In the present study, we further investigated whether transplantation of rat adrenal chromaffin cells seeded on microcarrier beads into the striatum of 6-hydroxydopamine-induced hemiparkinsonian rats would result in a sustained functional recovery. Behavioral tests using the apomorphine-induced rotational and elevated body swing tests up to 12 months posttransplantation revealed a significant behavioral recovery in animals that received adrenal chromaffin cells seeded on microcarrier beads compared to animals that received adrenal chromaffin cells alone, medium alone, or beads alone. Histological examination of tissue at 14 months posttransplantation revealed evidence of tyrosine hydroxylase-positive cells and an on-going glial response in animals transplanted with adrenal chromaffin cells seeded on microcarrier beads, in contrast to absence of such immunoreactive responses in the other groups. These findings support a facilitator role for microcarrier beads in transplantation of adrenal chromaffin cells or other cells that are easily rejected by the CNS.

This study was designed to explore the efficacy of a human clone cell line as an alternative neural graft source and to validate the practice of cryopreservation and xenografting as logistical approaches toward conducting neural transplantation. We investigated the biological effects of transplanting cultured human neurons (NT2N cells) derived from a well-characterized embryonal carcinoma cell line into the brains of rats subjected to transient, focal cerebral ischemia induced by embolic occlusion of the middle cerebral artery. At 1 month and extending throughout the 6-month posttransplantation test period, ischemic animals that were transplanted with NT2N cells and treated with an immunosuppressive drug displayed a significant improvement in a passive avoidance task as well as a normalization of asymmetrical motor behavior compared to ischemic animals that received rat fetal cerebellar cell grafts or vehicle alone. Remarkably, cryopreserved NT2N cell grafts, compared with fresh NT2N cell grafts, remained viable in the immunosuppressed rat brain and effective in producing behavioral recovery in immunosuppressed ischemic animals. The long-term viability of cryopreserved NT2N cell xenograftsin vivoand their sustained effectiveness in promoting behavioral recovery suggest potential utilization of xenografting and cryopreservation as useful protocols for establishing clone cell lines as graft source in neural transplantation therapies for central nervous system disorders.

The use of cyclosporine-A (CsA) immunosuppression for neural transplantation has become the treatment of choice for ameliorating host-graft rejection responses in human and animal transplant studies. However, the cytotoxic effects of CsA have warranted a search for alternative methods of protecting neural transplants. Sertoli cells produce an immunosuppressant factor, Fas ligand (Fas-L), that may provide the testis with its immunoprivileged status. Therefore, it has recently been suggested that these cells may be useful in producing localized immunosuppression for transplants. If Sertoli cells do produce localized immunosuppression, then it should be possible to successfully transplant Sertoli cells without additional immunosuppression following transplant surgery. The present study was undertaken to determine whether rat or porcine Sertoli cells transplanted into rat brain would survive for an extended period of time without CsA immunosuppression. Isolated rat or porcine Sertoli cells prelabeled with DiI were transplanted into normal rat brain. We report that both rat Sertoli cell allografts and porcine Sertoli cell xenografts survived for at least 2 months posttransplantation into the rat brain without CsA immunosuppression, indicating that these grafts were capable of producing sufficient localized immunosuppression to survive at the site of transplant without additional systemic immunosuppression.

Recently, we demonstrated amelioration of behavioral deficits associated with 6-hydroxydopamine-induced hemiparkinsonism by transplanting rat testis-derived Sertoli cells into adult male rat brains. In the present study, we used adult female hemiparkinsonian rats to investigate whether the beneficial effects of transplantation of Sertoli cells may be differentially affected by gender of the animal transplant recipient. At 1 month posttransplantation, animals transplanted with Sertoli cells showed functional recovery as revealed by significant reductions in apomorphine-induced rotational behavior and asymmetrical elevated body swing behavior. Control animals that received medium alone did not display any visible behavioral recovery. These results suggest that transplantation of Sertoli cells is not male hormone-dependent and further support the use of these cells as a graft source for Parkinson's disease and other neurological disorders.

(-)-Nicotine was shown to produce in vivo protection against neurobehavioral effects caused by systemically administered kainic acid (KA), an excitotoxin that has been widely used to induce temporal lobe convulsions including "wet dog shakes" in experimental animals. Rats pretreated with (-)-nicotine (0.5 mg/kg sc) 15 min before receiving KA (12.0 mg/kg sc) exhibited a marked reduction (P < 0.5) in the number of wet dog shakes when compared to saline-pretreated rats. Similarly, little visible brain damage was found in the (-)-nicotine-pretreated rats, but a widespread reduction in acetylcholinesterase-positive neurons was noted in the hippocampal areas of the saline-pretreated animals. While the mechanism of neuroprotection of (-)-nicotine is still not known, these findings suggest that (-)-nicotine may act as a therapeutic agent for putative excitotoxin-mediated disorders.