Collagen-chitosan scaffold impregnated with bone marrow mesenchymal stem cells for treatment of traumatic brain injury

Combinations of biomaterials and cells can effectively target delivery of cells or other therapeutic factors to the brain to rebuild damaged nerve pathways after brain injury.Porous collagen-chitosan scaffolds were prepared by a freeze-drying method based on brain tissue engineering.The scaffolds were impregnated with rat bone marrow mesenchymal stem cells.A traumatic brain injury rat model was established using the 300 g weight free fall impact method.Bone marrow mesenchymal stem cells/collagen-chitosan scaffolds were implanted into the injured brain.Modified neurological severity scores were used to assess the recovery of neurological function.The Morris water maze was employed to determine spatial learning and memory abilities.Hematoxylin-eosin staining was performed to measure pathological changes in brain tissue.Immunohistochemistry was performed for vascular endothelial growth factor and for 5-bromo-2-deoxyuridine(BrdU)/neuron specific enolase and BrdU/glial fibrillary acidic protein.Our results demonstrated that the transplantation of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds to traumatic brain injury rats remarkably reduced modified neurological severity scores,shortened the average latency of the Morris water maze,increased the number of platform crossings,diminished the degeneration of damaged brain tissue,and increased the positive reaction of vascular endothelial growth factor in the transplantation and surrounding areas.At 14 days after transplantation,increased BrdU/glial fibrillary acidic protein expression and decreased BrdU/neuron specific enolase expression were observed in bone marrow mesenchymal stem cells in the injured area.The therapeutic effect of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds was superior to stereotactic injection of bone marrow mesenchymal stem cells alone.To test the biocompatibility and immunogenicity of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds,immunosuppressive cyclosporine was intravenously injected 12 hours before transplantation and 1-5 days after transplantation.The above indicators were similar to those of rats treated with bone marrow mesenchymal stem cells and collagen-chitosan scaffolds only.These findings indicate that transplantation of bone marrow mesenchymal stem cells in a collagen-chitosan scaffold can promote the recovery of neuropathological injury in rats with traumatic brain injury.This approach has the potential to be developed as a treatment for traumatic brain injury in humans.All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medical University,China(approval No.AEEI-2015-035)in December 2015.     

Bone marrow mesenchymal stem cells repair spinal cord ischemia/reperfusion injury by promoting axonal growth and anti-autophagy

Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after trans- plantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-as- sociated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Fur- thermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neuro- filament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mes- enchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury.     

660 nm red light-enhanced bone marrow mesenchymal stem cell transplantation for hypoxic-ischemic brain damage treatment

Bone marrow mesenchymal stem cell transplantation is an effective treatment for neonatal hypoxic-ischemic brain damage. However, the in vivo transplantation effects are poor and their survival, colonization and differentiation efficiencies are relatively low. Red or near-infrared light from 600–1,000 nm promotes cellular migration and prevents apoptosis. Thus, we hypothesized that the combination of red light with bone marrow mesenchymal stem cell transplantation would be effective for the treatment of hypoxic-ischemic brain damage. In this study, the migration and colonization of cultured bone marrow mesenchymal stem cells on primary neurons after oxygen-glucose deprivation were detected using Transwell assay. The results showed that, after a 40-hour irradiation under red light-emitting diodes at 660 nm and 60 mW/cm2, an increasing number of green fluorescence-labeled bone marrow mesenchymal stem cells migrated towards hypoxic-ischemic damaged primary neurons. Meanwhile, neonatal rats with hypoxic-ischemic brain damage were given an intraperitoneal injection of 1 × 106 bone marrow mesenchymal stem cells, followed by irradiation under red light-emitting diodes at 660 nm and 60 mW/cm2 for 7 successive days. Shuttle box test results showed that, after phototherapy and bone marrow mesenchymal stem cell transplantation, the active avoidance response rate of hypoxic-ischemic brain damage rats was significantly increased, which was higher than that after bone marrow mesenchymal stem cell transplantation alone. Experimental findings indicate that 660 nm red light emitting diode irradiation promotes the migration of bone marrow mesenchymal stem cells, thereby enhancing the contribution of cell transplantation in the treatment of hypoxic-ischemic brain damage.     

Adenosine uptake sites in brain: regional distribution of putative subtypes in relationship to adenosine A1-receptors

Adenosine uptake sites have been characterized and localized in guinea pig and pointer dog brain by in vitro autoradiography, using as probes 3H-nitrobenzylthioinosine (3H-NBI) and the recently available 3H-dipyridamole (3H-DPR). In guinea pig brain and, to a lesser extent, in pointer dog brain, 3H-DPR was found to label more high-affinity binding sites than 3H-NBI and NBI inhibited 3H-DPR binding having pseudo-Hill coefficients smaller than 0.5. 3H-DPR and 3H-NBI labeled brain structures with different intensities in guinea pig brain, as was revealed by quantitative analysis. While the intensity of 3H-DPR binding varied about 4-fold in neuron-containing structures, 8-fold differences were observed for 3H-NBI binding with phylo- and ontogenetically older brain areas such as hypothalamus and various brain stem structures showing relatively higher densities. These findings raise the interesting possibility of adenosine uptake site heterogeneity (NBI-sensitive and insensitive) in guinea pig brain, complementing the well-established adenosine receptor heterogeneity (A1 and A2). As adenosine's neurodepressant effects are believed to be mainly mediated by adenosine A1-receptors, these were localized using 3H-cyclohexyl-adenosine (3H-CHA) as a ligand probe. In guinea pig brain, the highest receptor densities were seen in hippocampus and claustrum, while only relatively low levels were found in hypothalamus and various brain stem structures. As was previously described for rat brain, major discrepancies in the regional distribution of adenosine A1-receptors and adenosine uptake sites, as labeled by 3H-NBI, were seen in guinea pig brain. These discrepancies were only partly abolished (e.g., in cerebellum) by the use of 3H-DPR as an additional ligand probe for adenosine uptake sites. Adenosine uptake site heterogeneity, therefore, probably does not explain the previously described discrepancies in rodent brain between the distribution of adenosine A1-receptors and uptake sites. Because of the low affinity of 3H-DPR for adenosine uptake sites in rat and mouse brain, these species could not be investigated with this new radioligand probe. In pointer dog brain, as compared to guinea pig brain, a more similar distribution pattern of adenosine A1-receptors and adenosine uptake sites in the brain structures investigated (e.g., hippocampus) could be observed. The situation in guinea pig brain can, therefore, not be universalized to other species.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of intravenous transplantation of bone marrow mesenchymal stem cells on neurotransmitters and synapsins in rats with spinal cord injury

Bone marrow mesenchymal stem cells were isolated, purified and cultured in vitro by Percoll density gradient centrifugation combined with the cell adherence method. Passages 3-5 bone marrow mesenchymal stem cells were transplanted into rats with traumatic spinal cord injury via the caudal vein. Basso-Beattie-Bresnahan scores indicate that neurological function of experimental rats was significantly improved over transplantation time (1-5 weeks). Expressions of choline acetyltransferase, glutamic acid decarboxylase and synapsins in the damaged spinal cord of rats was significantly increased after transplantation, determined by immunofluorescence staining and laser confocal scanning microscopy. Bone marrow mesenchymal stem cells that had migrated into the damaged area of rats in the experimental group began to express choline acetyltransferase, glutamic acid decarboxylase and synapsins, 3 weeks after transplantation. The Basso-Beattie- Bresnahan scores positively correlated with expression of choline acetyltransferase and synapsins. Experimental findings indicate that intravenously transplanted bone marrow mesenchymal stem cells traverse into the damaged spinal cord of rats, promote expression of choline acetyltransferase, glutamic acid decarboxylase and synapsins, and improve nerve function in rats with spinal cord injury.     

Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury

Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5-bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury.     

Influence of age on BDNF modulation of hippocampal synaptic transmission: interplay with adenosine A2A receptors

We previously reported that adenosine, through A(2A) receptor activation, potentiates synaptic actions of brain-derived neurotrophic factor (BDNF) in the hippocampus of infant (3-4 weeks) rats. Since A(2A)-receptor-mediated actions are more evident in old than in young rats and since the therapeutic potential for BDNF-based strategies is greater in old subjects, we now evaluated synaptic actions of BDNF and the levels of TrkB receptors and of adenosine A(2A) receptors in the hippocampus of three groups of adult rats: young adults (10-16 weeks), old adults (36-38 weeks), and aged (70-80 weeks), as well as in one group of infant (3-4 weeks) rats. BDNF (20 ng/ml) enhances field excitatory postsynaptic potentials recorded from the hippocampus of young adults and aged rats, an action triggered by adenosine A(2A) receptor activation, since it was blocked by the A(2A) receptor antagonist, ZM 241385. In the other groups of animals BDNF (20 ng/ml) was virtually devoid of action on synaptic transmission. Western blot analysis of receptor density shows decreased amounts of TrkB receptors in old adults and aged rats, whereas A(2A) receptor levels assayed by ligand binding are enhanced in the hippocampus of old adults and aged rats. It is concluded that age-related changes in the density of TrkB receptors and of adenosine A(2A) receptors may be responsible for a nonmonotonous variation of BDNF actions on synaptic transmission in the hippocampus.     

Comparative hydrolysis of extracellular adenine nucleotides and adenosine in synaptic membranes from porcine brain cortex, hippocampus, cerebellum and medulla oblongata

We have investigated the metabolism of extracellular adenine nucleotides and adenosine in porcine brain. The cortex synaptic plasma membranes hydrolyzed ATP to ADP, AMP and adenosine. We also observed a slow hydrolysis of adenosine with the concomitant accumulation of inosine. These results indicate that NTPDase1, NTPDase2, ecto-5'-nucleotidase, and adenosine deaminase are present in cortex synaptic membranes from porcine brain. We further showed that all these enzymes are also abundant in synaptic membranes from hippocampus, cerebellum, and medulla oblongata and compared their specific activities. Brain cortex and hippocampus exhibited higher activities of NTPDase1 and NTPDase2 than cerebellum and medulla oblongata. It was consistent with the high level of the expression of NTPDases in the two first structures. Adenosine deaminase activity was found in all brain structures analyzed; however, it was lower than the activity of ecto-nucleotidases. Taken together, our data suggest that investigated enzymes have a ubiquitous abundance in porcine brain, and observed differences in their activities in cortex, hippocampus, cerebellum, and medulla oblongata may correlate with the pattern of P2 receptor expression in these brain areas. In addition, low activity of adenosine deaminase may indicate that nonenzymatic mechanism(s) are responsible for the termination of P1 receptor signaling in porcine brain.     

Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model

Neuroplasticity subsequent to functional angiogenesis is an important goal for cell-based therapy of ischemic neural tissues. At present, the cellular and molecular mechanisms involved are still not well understood. In this study, we isolated mesenchymal stem cells (MSCs) from Wharton's jelly (WJ) to obtain clonally expanded human umbilical cord-derived mesenchymal stem cells (HUCMSCs) with multilineage differentiation potential. Experimental rats receiving intracerebral HUCMSC transplantation showed significantly improved neurological function compared to vehicle-treated control rats. Cortical neuronal activity, as evaluated by proton MR spectroscopy (1H-MRS), also increased considerably in the transplantation group. Transplanted HUCMSCs migrated towards the ischemic boundary zone and differentiated into glial, neuronal, doublecortin+, CXCR4+, and vascular endothelial cells to enhance neuroplasticity in the ischemic brain. In addition, HUCMSC transplantation promoted the formation of new vessels to increase local cortical blood flow in the ischemic hemisphere. Modulation by stem cell-derived macrophage/microglial interactions, and increased beta1-integrin expression, might enhance this angiogenic architecture within the ischemic brain. Inhibition of beta1-integrin expression blocked local angiogenesis and reduced recovery from neurological deficit. In addition, significantly increased modulation of neurotrophic factor expression was also found in the HUCMSC transplantation group. In summary, regulation of beta1-integrin expression plays a critical role in the plasticity of the ischemic brain after the implantation of HUCMSCs.     

Transplantation of Nogo-66 receptor gene-silenced cells in a poly(D,L-lactic-co-glycolic acid) scaffold for the treatment of spinal cord injury

Inhibition of neurite growth,which is in large part mediated by the Nogo-66 receptor,affects neural regeneration following bone marrow mesenchymal stem cell transplantation.The tissue engineering scaffold poly(D,L-lactide-co-glycolic acid) has good histocompatibility and can promote the growth of regenerating nerve fibers.The present study used small interfering RNA to silence Nogo-66 receptor gene expression in bone marrow mesenchymal stem cells and Schwann cells,which were subsequently transplanted with poly(D,L-lactide-co-glycolic acid) into the spinal cord lesion regions in rats.Simultaneously,rats treated with scaffold only were taken as the control group.Hematoxylin-eosin staining and immunohistochemistry revealed that at 4 weeks after transplantation,rats had good motor function of the hind limb after treatment with Nogo-66 receptor gene-silenced cells plus the poly(D,L-lactide-co-glycolic acid) scaffold compared with rats treated with scaffold only,and the number of bone marrow mesenchymal stem cells and neuron-like cells was also increased.At 8 weeks after transplantation,horseradish peroxidase tracing and transmission electron microscopy showed a large number of unmyelinated and myelinated nerve fibers,as well as intact regenerating axonal myelin sheath following spinal cord hemisection injury.These experimental findings indicate that transplantation of Nogo-66 receptor gene-silenced bone marrow mesenchymal stem cells and Schwann cells plus a poly(D,L-lactide-co-glycolic acid) scaffold can significantly enhance axonal regeneration of spinal cord neurons and improve motor function of the extremities in rats following spinal cord injury.     

Bone marrow mesenchymal stem cells with Nogo-66 receptor gene silencing for repair of spinal cord injur y

We hypothesized that RNA interference to silence Nogo-66 receptor gene expression in bone marrow mesenchymal stem cells before transplantation might further improve neurological function in rats with spinal cord transection injury. After 2 weeks, the number of neurons and BrdU-positive cells in the Nogo-66 receptor gene silencing group was higher than in the bone marrow mesenchymal stem cell group, and significantly greater compared with the model group. After 4 weeks, behavioral performance was signiifcantly enhanced in the model group. Af-ter 8 weeks, the number of horseradish peroxidase-labeled nerve ifbers was higher in the Nogo-66 receptor gene silencing group than in the bone marrow mesenchymal stem cell group, and signiifcantly higher than in the model group. The newly formed nerve ifbers and myelinated ner ve ifbers were detectable in the central transverse plane section in the bone marrow mesenchymal stem cell group and in the Nogo-66 receptor gene silencing group.     

Chronic theophylline treatment increases adenosine A1, but not A2, receptor binding in the rat brain: an autoradiographic study.

Chronic exposure to adenosine receptor antagonists results in an upregulation of brain adenosine A1 receptors as measured by traditional radioligand binding techniques. In the present study, quantitative receptor autoradiography was used to characterize alterations in rat brain adenosine A1 and A2 receptors following the repeated administration of high doses of theophylline. Daily administration of theophylline (75 or 100 mg/kg) markedly increased (125-150% of control) 1 nM [3H]cyclohexyladenosine binding to adenosine A1 receptors in specific cellular layers of the hippocampus, thalamus, and cerebellum with other brain regions showing more moderate increases in binding. By contrast, this chronic theophylline treatment did not produce any significant alterations in the binding of 4 nM [3H]CGS 21680 to adenosine A2 receptors, which were exclusively localized in the striatal region. This apparent differential sensitivity of adenosine receptor subtypes to chronic antagonist treatment suggests a possible intrinsic difference in the regulation of these receptor subtypes which may also be specific to particular brain regions. These results are discussed in relationship to other recent observations, indicating that the pattern of agonist binding to adenosine receptors may be regulated by a differential extent of coupling between adenosine receptors and G-binding proteins in different brain regions.     

干细胞移植对大脑中动脉闭塞模型鼠脑组织miR-34a及survivin表达的影响

目的观察骨髓间充质干细胞(BMSCs)移植对缺血再灌注损伤后大鼠脑组织miR-34a和survivin表达的影响,探讨BMSCs移植的抗凋亡和神经保护作用机制。方法将192只大鼠随机分为空白组、模型组、PBS液移植组和干细胞移植组;采用改良Longa线栓法制作大鼠大脑中动脉闭塞再灌注(MCAO)模型;通过尾静脉注射法行干细胞移植;改良大鼠神经功能缺损评分(m NSS)评估神经功能缺损;免疫组化检测survivin的表达;实时荧光定量PCR技术检测miR-34a的表达。结果干细胞移植组的神经功能缺损评分在12 h、1 d时与模型组比较无明显差异(P0.05);3 d、7 d时明显低于模型组(P0.05)。干细胞移植组的survivin阳性细胞率在各时间点均显著高于模型组(P0.05)。干细胞移植组的miR-34 a表达量在各时间点均显著低于模型组(P0.01)。结论大鼠脑缺血-再灌注损伤可致病灶区miR-34 a的表达上调;干细胞移植可明显改善脑缺血-再灌注大鼠的神经功能;移植干细胞可能通过下调病灶区miR-34a和上调survivin的表达发挥抗凋亡及神经保护作用。     

Adenosine A3 receptors are located in neurons of the rat hippocampus

Adenosine is a neuromodulator acting mainly via inhibitory A1 and facilitatory A2A receptors. Whole tissue PCR also identified adenosine A3 receptors in the brain and A3 receptor agonists affect CNS neuronal responses and viability. However, recent reports failed to detect A3 receptor expression in CNS neurons and showed that A3 receptor agonists can bind and activate A1 receptors. We now present evidence for the presence of A3 receptor mRNA in CNS neurons using single cell PCR analysis of laser dissected hippocampal neurons. Western blot analysis showed that A3 receptors are present in rat hippocampal nerve terminal membranes. This indicates that A3 receptors are present in CNS neurons in the hippocampus.     

Glutamate receptor subunits expression in memory-associated brain structures: regional variations and effects of aging

We investigated regional variations and the effects of aging on the expression of the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor subunits in several memory-associated structures using Western blotting. In young adult rats, NR1, NR2A, and GluR2 levels varied between the hippocampus and parahippocampal region and between the subregions of the hippocampus. When a comparison was made between young (4-month-old) and aged (24-month-old) rats, significant decreases in NR1 expression were found in the aged ventral hippocampus and the entorhinal and postrhinal cortices. There were significant decreases in NR2A expression in the aged parahippocampal region, but not in the hippocampus. The expression of the GluR2 subunit was significantly reduced in the ventral hippocampus and the postrhinal cortex. A dramatic decrease in NR1 and GluR2 expression was found in the aged CA2/3 and CA1, respectively, but there were no significant age-related changes in NR2A expression. All three subunits were expressed at a similar level in the two age groups in the prefrontal cortex. These results suggest differential expression and effects of aging on NMDA and AMPA receptor subunits in memory-associated brain structures.     

Endothelin-A receptor antagonists prevent amyloid-β-induced increase in ETA receptor expression, oxidative stress, and cognitive impairment

Alzheimer's disease is a neurodegenerative disorder associated with abnormal accumulation of amyloid-β (Aβ) which can release endothelin (ET). The present study was conducted to investigate the effect of ET antagonists on Aβ-induced changes in ETA and ETB receptor expression, oxidative stress, and cognitive impairment. Male Sprague-Dawley rats were treated with Aβ1-40 in the lateral cerebral ventricles and were administered vehicle or ET antagonists for 14 days. Aβ treatment produced an increase in ETA receptor expression in the cerebral cortex, hippocampus, and brain stem by 72%, 85%, and 90%, respectively. No change in ETB receptor expression was observed. There was an increase in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and superoxide dismutase (SOD) levels in Aβ-treated rats. In the Morris swim task, Aβ treated rats showed a significant impairment in spatial memory. ET receptor antagonists, BQ123, BMS182874, and TAK-044, significantly decreased Aβ-induced increase in ETA expression in the cortex, hippocampus, and brain stem. Rats treated with ET antagonists showed significant attenuation of Aβ-induced changes in the brain MDA, GSH, and SOD levels. Rats treated with specific ETA receptor antagonists, BQ123 and BMS182874, significantly reduced the cognitive impairment induced by Aβ. However, nonspecific ETA/ETB receptor antagonist TAK-044 did not show any improvement in the learning and memory parameter. This study demonstrates that ETA receptor antagonists are effective in preventing cognitive impairment, changes in ETA expression and oxidative stress induced by Aβ. It is concluded that ETA receptor antagonists may be useful in improving cognitive impairment due to Alzheimer's disease.     

Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells

C. Nicaise, D. Mitrecic and R. Pochet (2011) Neuropathology and Applied Neurobiology 37, 179–188
Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells Stem cell research raises hopes for incurable neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), affecting the motoneurones of the central nervous system (CNS), stem cell‐based therapy aims to replace dying host motoneurones by transplantation of cells in disease‐affected regions. Moreover, transplanted stem cells can serve as a source of trophic factors providing neuroprotection, slowing down neuronal degeneration and disease progression. Aim: To determine the profile of seven trophic factors expressed by mesenchymal stem cells (MSC) and neural stem cells (NSC) upon stimulation with CNS protein extracts from SOD1‐linked ALS rat model. Methods: Culture of rat MSC, NSC and fibroblasts were incubated with brain and spinal cord extracts from SOD1(G93A) transgenic rats and mRNA expression of seven growth factors was measured by quantitative PCR. Results: MSC, NSC and fibroblasts exhibited different expression patterns. Nerve growth factor and brain‐derived neurotropic factor were significantly upregulated in both NSC and MSC cultures upon stimulation with SOD1(G93A) CNS extracts. Fibroblast growth factor 2, insulin‐like growth factor and glial‐derived neurotropic factor were upregulated in NSC, while the same factors were downregulated in MSC. Vascular endothelial growth factor A upregulation was restricted to MSC and fibroblasts. Surprisingly, SOD1(G93A) spinal cord, but not the brain extract, upregulated brain‐derived neurotropic factor in MSC and glial‐derived neurotropic factor in NSC. Conclusions: These results suggest that inherent characteristics of different stem cell populations define their healing potential and raise the concept of ALS environment in stem cell transplantation.     

Therapeutic potential of dental pulp stem cell transplantation in a rat model of Alzheimer’s disease

Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest. They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors. Few studies have reported Alzheimer’s disease treatment using dental pulp stem cells. Rat models of Alzheimer’s disease were established by injecting amyloid-β1–42 into the hippocampus. Fourteen days later, 5 × 10⁶ dental pulp stem cells were injected into the hippocampus. Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin, NeuN, and neurofilament 200 in the hippocampus, while the expression of amyloid-β was decreased. Moreover, cognitive and behavioral abilities were improved. These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins, which indicates a potential therapeutic effect for Alzheimer’s disease. This study was approved by the Animal Ethics Committee of Harbin Medical University, China (approval No. KY2017-132) on February 21, 2017.

Chinese Library Classification No. R456; R741; Q2     

Anticonvulsant effect of bilateral injection of N6-cyclohexyladenosine into the CA1 region of the hippocampus in amygdala-kindled rats.

In this study the role of adenosine A(1) receptors of CA1 region of the hippocampus on amygdala-kindled seizures was investigated in rats. Results obtained showed that in kindled animals, bilateral injection of N(6)-cyclohexyladenosine (CHA), an adenosine A(1) receptor agonist, at doses of 0.1, 1 and 10 microM into the CA1 region of the hippocampus significantly decreased the afterdischarge duration and stage 5 seizure duration and increased the latency to stage 4 seizure, but there were no changes in seizure stage. Also, bilateral injection of 1,3-dimethyl-8-cyclopenthylxanthine (CPT), an adenosine A(1) receptor antagonist, at doses of 0.5 and 1 microM into the CA1 region of the hippocampus could not produce any changes in the seizure parameters. Intrahippocampal pretreatment of CPT (1 microM) before CHA (0.1 and 1 microM), reduced the effects of CHA on seizure parameters significantly. Thus, it may be suggested that CA1 region of the hippocampus plays an important role in spreading seizure spikes from the amygdala to other brain regions and activation of adenosine A(1) receptors in this region, participates in anticonvulsant effects of adenosine agonists.     

Localisation of the adenosine uptake site in the human brain: a comparison with the distribution of adenosine Al receptors

Using quantitative receptor autoradiography we investigated the distribution of the adenosine uptake site labelled with [³H]NBTI in post-mortem human brain and compared its distribution with that of the A1 adenosine receptor labelled with [³H]CHA. The highest levels of [3H]NBTI binding were found in the cortex and striatum, with moderate levels in the hippocampus, globus pallidus, cerebellum and some midbrain and spinal cord nuclei. The distribution of A1 receptors and this adenosine uptake site differed in the hippocampus where A1 receptors were highest in CAI but the uptake site was low in CA1 and higher in the molecular layer of the dentate gyrus. These results define the anatomical distribution of the high affinity NBTI sensitive adenosine uptake site in the normal human brain.