Central Nervous Tissue Research Articles

ボルナウイルス

Bornaviridae is an enveloped animal virus carrying an 8.9 kb non-segmented, negative-strand RNA genome. The genus bornavirus contains two members infecting vertebrates, Borna disease virus (BDV) and avian bornavirus (ABV), which could preferably infect the nervous systems. BDV causes classical Borna disease, a progressive meningoencephalomyelitis, in horses and sheep, and ABV is known to induce proventricular dilatation disease, a fatal disease characterized by a lymphocytic, plasmacytic inflammation of central and peripheral nervous tissues, in multiple avian species. Recent evidences have demonstrated that bornavirus is unique among RNA viruses as they not only establish a long-lasting, persistent infection in the nucleus, but also integrate their own DNA genome copy into the host chromosome. In this review, I outline the recent knowledge about the unique virological characteristics of bornaviruses, as well as the diseases caused by the infection of BDV and ABV.

Structurally conserved C-RFa revealed prolactin releasing activity in vitro and gene expression changes in pituitary of seasonally acclimatized carp

Here we show the cloning and characterization of a novel homolog of prepro C-RFa cDNA from Cyprinus carpio. The deduced preprohormone precursor of 115 amino acids leads to a mature bioactive peptide of 20 amino acids with identical sequence to other teleost C-RFa. Modeling of the mature C-RFa peptide highlighted significant similarity to homologous human PrRP20, specifically the conserved amphipathic system defined by the C-terminal alpha-helix. Clearly, the synthetic C-RFa peptide stimulated prolactin release from primary cultured fish pituitary cells. For the first time, significant variation was shown in C-RFa mRNA and protein levels in the hypothalamus and pituitary between summer- and winter-acclimatized carp. Furthermore, C-RFa protein distribution in carp central nervous tissue was visualized by immunodetection in fibers and cells in hypothalamus, olfactory tract, cerebellum and pituitary stalk. In conclusion, we demonstrated the structure conservation of C-RFa in teleosts and mammals and immunopositive cells and fibers for C-RFa in brain areas. Finally, the increase of C-RFa expression suggests the participation of this hypothalamic factor in the mechanism of modulation in PRL expression in carp.

Abstract 9362: Argon Reduces Neurohistopathological Damage and Preserves Functional Recovery After Cardiac Arrest in Rats

Introduction: Xenon has profound neuroprotective effects in various models of neurological injury and is currently undergoing phase two clinical trials in cardiac arrest patients. However, xenon is very costly which might preclude a widespread use. We hypothesized that the more available Argon might also protect central nervous tissues and functional recovery in a rodent model of global cerebral ischemia. Material and Methods: 14 male Sprague-Dawley rats were subjected to 7 mins of cardiac arrest and 3 mins of cardiopulmonary resuscitation (CPR). One hour after successful CPR, animals were randomized to ventilation with 70% Argon for 1h in comparison to untreated controls receiving 70% Nitrogen. A neurologic deficit score was calculated on seven days following the experiment before the animals were killed and the brains harvested for histopathological analyses. Results: All animals survived. Untreated controls exhibited severe neurological dysfunction while animals from the Argon group showed significant improvements at all points in time (Fig. 1). This was paralleled by a significant reduction in the degree of necrotic cell damage in the neocortex and the hippocampal CA 3/4 region (Fig. 2). Conlusions: Our study demonstrates that a single one hour application of 70% Argon provided a significant reduction in histopathological damage of the neocortex and hippocampus which was associated with a marked improvement in functional neurological recovery.

Dissecting Cis Regulation of Gene Expression in Human Metabolic Tissues

Complex diseases such as obesity and type II diabetes can result from a failure in multiple organ systems including the central nervous system and tissues involved in partitioning and disposal of nutrients. Studying the genetics of gene expression in tissues that are involved in the development of these diseases can provide insights into how these tissues interact within the context of disease. Expression quantitative trait locus (eQTL) studies identify mRNA expression changes linked to proximal genetic signals (cis eQTLs) that have been shown to affect disease. Given the high impact of recent eQTL studies, it is important to understand what role sample size and environment plays in identification of cis eQTLs. Here we show in a genotyped obese human population that the number of cis eQTLs obey precise scaling laws as a function of sample size in three profiled tissues, i.e. omental adipose, subcutaneous adipose and liver. Also, we show that genes (or transcripts) with cis eQTL associations detected in a small population are detected at approximately 90% rate in the largest population available for our study, indicating that genes with strong cis acting regulatory elements can be identified with relatively high confidence in smaller populations. However, by increasing the sample size we allow for better detection of weaker and more distantly located cis-regulatory elements. Yet, we determined that the number of tissue specific cis eQTLs saturates in a modestly sized cohort while the number of cis eQTLs common to all tissues fails to reach a maximum value. Understanding the power laws that govern the number and specificity of eQTLs detected in different tissues, will allow a better utilization of genetics of gene expression to inform the molecular mechanism underlying complex disease traits.

RB4CD12 epitope expression and heparan sulfate disaccharide composition in brain vasculature

RB4CD12 is a phage display antibody that recognizes a heparan sulfate (HS) glycosaminoglycan epitope. The epitope structure is proposed to contain a trisulfated disaccharide, [-IdoA(2-OSO(3))-GlcNSO(3) (6-OSO(3))-], which supports HS binding to various macromolecules such as growth factors and cytokines in central nervous tissues. Chemically modified heparins that lack the trisulfated disaccharides failed to inhibit the RB4CD12 recognition of HS chains. To determine the localization of the RB4CD12 anti-HS epitope in the brain, we performed an immunohistochemical analysis for cryocut sections of mouse brain. The RB4CD12 staining signals were colocalized with laminin and were detected abundantly in the vascular basement membrane. Bacterial heparinases eliminated the RB4CD12 staining signals. The RB4CD12 epitope localization was confirmed by immunoelectron microscopy. Western blotting analysis revealed that the size of a major RB4CD12-positive molecule is ∼460 kDa in a vessel-enriched fraction of the mouse brain. Disaccharide analysis with reversed-phase ion-pair HPLC showed that [-IdoA(2-OSO(3))-GlcNSO(3) (6-OSO(3))-] trisulfated disaccharide residues are present in HS purified from the vessel-enriched brain fraction. These results indicated that the RB4CD12 anti-HS epitope exists in large quantities in the brain vascular basement membrane.

Rapidly Progressive Creutzfeldt-Jakob Disease VV1 Subtype

Creutzfeldt-Jakob disease (CJD) is rare transmissible spongiform encephalopathy caused by abnormal, host-encoded prion proteins that accumulate in the central nervous tissue. CJD occurs in 3 forms: sporadic, familial and acquired (iatrogenic and variant). Six different molecular subtypes (MM1, MM2, MV1, MV2, VV1, and VV2) of sporadic CJD (sCJD) have been identified by genotype at codon 129. The VV1 type represents one of the rarest subtyp es. In contrast to the classic sCJD types, these patients are characterized by young age at onset, and slowly progressive dementia. Our case illustrates that sCJD VV1 subtype can have a rapid progression. A 50 year old Caucasian presented with memory loss and personality changes. Magnetic resonance imaging of the brain showed increased signal intensity in the grey mater of cerebral cortex. Brain biopsy confirmed the diagnosis of sCJD VV1 subtype. Currently there is no effective treatment and patient succumbed to death within 3 months of presentation. doi:10.4021/jmc221w

Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro

In addition to its function as a regulator of hematopoiesis, the cytokine erythropoietin (Epo) initiates adaptive cellular responses to both moderate environmental challenges and tissue damaging insults in various non-hematopoietic mammalian tissues. Epo's neuroprotective and neuroregenerative functions mediated through janus kinases (JAK)/signal transducers and activators of transcription (STAT) transduction pathways and regulation of Epo and Epo receptor expression in the nervous system by hypoxia inducible factor (HIF) have been documented in a variety of in vitro and in vivo studies and homologs of the human Epo gene are present in fish, amphibians and mammals. The present study reproduces the hallmarks of Epo-mediated mammalian neuroprotection in the grasshopper nervous system. Recombinant human Epo (rhEpo) increases the survival of dissociated grasshopper brain neurons under normoxic and hypoxic conditions and promotes the regeneration of neurites in vitro. In addition, reestablishment of sound source localization after unilateral tympanic nerve crush injury was accelerated and more complete after application of rhEpo, demonstrating in vivo support of auditory receptor cell axon regeneration. Immunoblots of central nervous tissue extracts from mouse, grasshopper, crayfish and leech labeled protein bands of ∼38 kDa, fitting to the molecular weight of Epo reported in earlier studies. These results indicate that a ligand/receptor system that shares structural and functional similarities with mammalian Epo and Epo receptor exerts neuroprotective and neuroregenerative effects in insects. With both upstream (HIF system) and downstream (JAK/STAT pathway) elements of the mammalian Epo system being present in insects and other invertebrates, Epo-like signaling involved in tissue protection appears to be an ancient beneficial function shared by vertebrates and invertebrates.

Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy

Painful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporter (5-HTT−/− mice) after inducing neuropathy by intraperitoneal injections of VCR. We used standard tests for evoked pain, high performance liquid chromatography to measure serotonin (5-HT), and immunohistochemistry of L4/5 dorsal root ganglia (DRG) to assess neuronal injury and inflammation. After injections of VCR, 5-HTT−/− mice did not develop hypersensitivity to heat, in contrast to their wildtype (wt) littermates ( p < 0.05). Also, 5-HTT−/− mice recovered faster from mechanical hypersensitivity than wt mice ( p < 0.05). 5-HT levels were lower in the peripheral and central nervous tissue of vehicle or VCR-treated 5-HTT−/− mice compared to wt mice. VCR-treated mice had higher numbers of injured neurons as identified by immunostaining for activating transcription factor 3, and more immunoreactive macrophages in the L4/5 DRG than vehicle-treated mice. There was no difference between genotypes. Thus the 5-HTT−/− genotype did not protect mice from VCR-induced neuronal injury and macrophage infiltration in the DRG. Our results suggest that the reduced peripheral 5-HT levels of 5-HTT−/− mice in VCR neuropathy underlie the lack of heat hyperalgesia. Conversely, attenuation of mechanical allodynia in 5-HTT−/− mice may indicate reduced 5-HT-mediated facilitation in the central nervous system.

Immunology of Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite. Following oral infection the parasite crosses the intestinal epithelial barrier to disseminate throughout the body and establish latent infection in central nervous tissues. The clinical presentation ranges from asymptomatic to severe neurological disorders in immunocompromised individuals. Since the clinical presentation is diverse and depends, among other factors, on the immune status of the host, in the present review, we introduce parasitological, epidemiological, clinical, and molecular biological aspects of infection with T. gondii to set the stage for an in-depth discussion of host immune responses. Since immune responses in humans have not been investigated in detail the present review is exclusively referring to immune responses in experimental models of infection. Systemic and local immune responses in different models of infection are discussed, and a separate chapter introduces commonly used animal models of infection.

Analysis of genetic diversity and amino acid sequence of HIV-1 tat from a patient with AIDS dementia complex

Objective To study the variation and characteristics of HIV-1 tat exon 1 gene from a patient with AIDS dementia complex（ ADC）, so as to research the pathogenesis of ADC. Methods The tat gene was amplified with nested PCR from genomic DNA which was extracted from lymph node, spleen and different brain tissues（ meninges, grey matter from frontal cortex, white matter from frontal cortex, temporal cortex and basal ganglia） of a patient who died of ADC. PCR products were cloned into the pGEM-T vector,after transformation and selection by ampicillin and blue/white spotting. Five of positive clones were sequenced. HIV-1 tat sequences were processed with BioEdit and MEGA4. With the softwares, Neighbor-Joining tree, p-Distances, values of ds/dn, and analysis of amino acid motifs were all done. Results The samples were all identified as HIV-1 B and genetic variation exists in HIV-1 tat isolated from different tissue;Compared with HXB2, sixteen sites of the amino acid seque nce coded by the HIV-1 tat gene which was isolated from the patient changed. In addition, part of the changes were different between periphery and brain,especially, the five Q54R changes from basal ganglia and one Q54R change from temporal cortex are deserve to follow with interest. Conclusion Variations exist in the HIV-1 tat genes extracted from the ADC patient and the variations from peripheral and central nerve tissues were different, whether the variations concerned with the pathogenesis of ADC need more research. Key words: Human immunodeficiency virus 1 （ HIV-1 ） HIV-1 tat AIDS dementia complex （ADC） Genetic diversity Amino acid sequence

Histone acetylation‐mediated glycosyltransferase gene regulation in mouse brain during development

Gangliosides are sialic acid-containing glycosphingolipids abundant in the central nervous tissues. The quantity and expression pattern of gangliosides in brain change drastically during early development and are mainly regulated through stage-specific expression of glycosyltransferase (ganglioside synthase) genes. It is still unclear, however, how the transcriptional activation of glycosyltransferase genes is regulated during development. In this study, we investigated the epigenetic regulation of two key glycosyltransferases, N-acetylgalactosaminyltransferase I (GA2/GM2/GD2/GT2-synthase) and sialyltransferase II (GD3-synthase), in embryonic, postnatal, and adult mouse brains. Combined bisulfite restriction analysis assay showed that DNA methylation in the 5' regions of these glycosyltransferase genes was not associated with their expression patterns. On the other hand, chromatin immunoprecipitation assay of both glycosyltransferase genes showed that their histone H3 acetylation was highly correlated to their mRNA expression levels during development. In fact, we confirmed that the expression patterns of gangliosides and glycosyltransferases in neuroepithelial cells were changed after treatment with a histone deacetylase inhibitor, sodium butyrate. Our studies provide the first evidence that efficient histone acetylation of the glycosyltransferase genes in mouse brain contributes to the developmental alteration of ganglioside expression.

Primary Central Nervous System Mucosa-Associated Lymphoid Tissue Lymphoma-Case Report-

A 55-year-old woman presented with an extremely rare primary central nervous system mucosa-associated lymphoid tissue (MALT) lymphoma manifesting as seizure and was subsequently diagnosed with dural MALT lymphoma in the cranium. Magnetic resonance imaging revealed a left frontal dural mass with peritumoral edema. Histological examination of the dural mass confirmed MALT lymphoma and revealed infiltration of small cells with irregular nuclear borders and expression of a B cell marker (CD20) but absence of CD5, CD10, CD23, and cyclinD1. Reactive T-cell infiltration was also seen. Subsequently, local irradiation (40 Gy/20 fractions) was performed. Magnetic resonance imaging showed complete remission just after irradiation was completed. There was no evidence of systemic MALT lymphoma. There has been no recurrence for 3 years without additional therapy.

Rapidly Progressive Creutzfeldt-Jakob Disease VV1 Subtype

Creutzfeldt-Jakob disease (CJD) is rare transmissible spongiform encephalopathy caused by abnormal, host-encoded prion proteins that accumulate in the central nervous tissue. CJD occurs in 3 forms: sporadic, familial and acquired (iatrogenic and variant). Six different molecular subtypes (MM1, MM2, MV1, MV2, VV1, and VV2) of sporadic CJD (sCJD) have been identified by genotype at codon 129. The VV1 type represents one of the rarest subtypes. In contrast to the classic sCJD types, these patients are characterized by young age at onset, and slowly progressive dementia. Our case illustrates that sCJD VV1 subtype can have a rapid progression. A 50 year old Caucasian presented with memory loss and personality changes. Magnetic resonance imaging of the brain showed increased signal intensity in the grey mater of cerebral cortex. Brain biopsy confirmed the diagnosis of sCJD VV1 subtype. Currently there is no effective treatment and patient succumbed to death within 3 months of presentation. J Med Cases. 2011;2(4):139-142 doi: https://doi.org/10.4021/jmc221w Normal 0 7.8 磅 0 2 false false false EN-US ZH-CN X-NONE

Heart Transplantation in 107 Cases of Chagas' Disease

Introduction Chagas' disease is endemic in South America. Objective This research reviewed the experience with cardiac transplantation in Chagas' disease, emphasizing reactivation, immunosuppression, and mortality. Methods Over 25 years from March 1985 to March 2010, 107/409 (26.2%) patients with Chagas' disease underwent heart transplantation, patients including 74 (71.1%) men and 72 (67.2%), in functional class IV with 33 (30.8%) on vasopressors and 17 (10.7%) on mechanical circulatory support. Results The diagnosis of disease reactivation was performed by identifying the parasite in the myocardium ( n = 23; 71.8%) in the subcutaneous tissue ( n = 8; 25.0%), in blood ( n = 11; 34.3%), or in central nervous tissue ( n = 1; 3.1%). Hospital mortality was 17.7% ( n = 19) due to infection ( n = 6; 31.5%), graft dysfunction ( n = 6; 31.5%), rejection ( n = 4; 21.1%), or sudden death ( n = 2; 10.5%). Late mortality was 27 (25.2%) cases, which were distributed as: rejection ( n = 6; 22.2%), infection ( n = 6; 22.2%), ( n = lymphoma 4; 14.8%), sarcoma ( n = 2; 7.4%), for constrictive pericarditis ( n = 2; 7.4%) reactivation of Chagas' disease in the central nervous system ( n = 1; 7.1%). Conclusions Transplantation in Chagas' disease has peculiar problems that differ from other etiologies due to the possibility of disease reactivation and the increased possibility of emergence of cancers. However, transplantation is the only treatment able to modify the natural progression of the disease in its terminal phase. Early diagnosis and rapid introduction of benzonidazole reverses the histological patterns. Immunosuppression, especially steroids, predisposes to the development of cancer and disease reactivation.

Neurogluten: patología neurológica por intolerancia al gluten

Gluten sensitivity is a systemic autoimmune disease that occurs in genetically susceptible individuals on ingesting gluten. It can appear at any age, then becoming a permanent condition. It is more frequent in women, as happens with other autoimmune diseases. Celiac disease is the intestinal form and the most important manifestation among a set of gluten-induced autoimmune pathologies that affect different systems. Neurological manifestations of gluten sensitivity, with or without enteropathy, are also frequent, their pathogenesis including an immunological attack on the central and peripheral nervous tissue accompanied by neurodegenerative changes. The clinical manifestations are varied, but the most common syndromes are cerebellar ataxia and peripheral neuropathy. Finally, gluten sensitivity is associated to a varying degree, with other complex diseases and could influence their evolution. The early detection of cases of gluten sensitivity with neurological manifestations and subsequent treatment with the gluten-free diet could provide remarkable benefits to the patients.

Repair of Excitotoxic Neuronal Damage Mediated by Neural Stem Cell Lysates in Adult Mice

The present study aimed to investigate a possibility of brain repair from diseased or damaged disorders mediated by cell-free filtrate of neural stem cell (NSC) lysates (FNSCL). Mouse NSCs were isolated from the brains of embryos at 15 day postcoitum (dpc). The expression of the Nestin was examined by immunocytochemical technique. Sonication of NSCs cultured and nestin-positive was performed in a bath-type sonicator, and the cell-free filtrate was recovered from a filtrative step of the lysates. The animals in the monosodium glutamate MSG group received intragastric(ig) administration of MSG (2.0 g/kg per day) for 10 days the animals in the MSG+NSCs and MSG+FNSCL groups received intracerebroventricular transplantation of 10 ?l of NSC suspension, approximately 1.0×105 cells, or intracerebroventricular injection of 10 ?l of cell-free filtrate of lysates of approximately 1.0×105 NSCs on day 1 and day 11 after 10-d MSG exposure, respectively. The mice in control and MSG group were intracerebroventricularly administered with 10 ?l of DMEM instead of NSCs or FNSCL. On 11 day after intracerebroventricular transplantation of NSCs or intracerebroventricular injection of FNSCL, the test of Y-maze discrimination learning were performed, and then the histopathology of the animal brains was studied, to analyze MSG-induced functional and morphological changes and the effects of intracerebroventricular transplantation of NSCs or intracerebroventricular injection of FNSCL on the brain repair from MSG-induced excitotoxic injury. Both intracerebroventricular transplantation of NSCs and intracerebroventricular injection of FNSCL facilitated the brain repair following glutamate-induced excitotoxic injury in adult mice, suggesting that there are certain NSC factors inside NSCs which are effective in repairing glutamate-induced excitotoxic brain injury. Administration of FNSCL might be a cell-free-based therapeutic strategy to repair diseased or damaged central nervous system CNS tissue.

Immunoperoxidase detection of neuronal antigens in full-thickness whole mount preparations of hollow organs and thick sections of central nervous tissue

Immunofluorescently stained whole mounts have proved useful for defining the innervation of the gut and large blood vessels. Nerves supplying other hollow organs are usually studied in sections, which provide much less information. Aiming to describe the entire innervation of rat uterus, we developed a method for immunoperoxidase staining of full-thickness whole mounts that allowed us to visualize all immunoreactive axons. Uterine horns were dissected out, slit open, stretched, pinned flat and fixed. Entire horns were treated with methanol/peroxide, buffered Triton X-100 and normal serum and then incubated in primary antibodies, biotinylated secondary antibodies and avidin-horseradish peroxidase (HRP), each for at least 3 days. Peroxidase reactions revealed immunoreactivity. Immunostained horns were dehydrated, infiltrated with epoxy resin, mounted on slides under Aclar coverslips and polymerized. We treated bladders, gut, major pelvic ganglia and thick sections of perfused medulla oblongata similarly to assess the applicability of the method. Using this method, we could map the entire uterine innervation provided by axons immunoreactive for a variety of antigens. We could also assess the entire tyrosine hydroxylase-immunoreactive innervation in all layers of bladder, gut and ganglia whole mounts and throughout 300 μm sections of medulla. These observations show that this method for immunoperoxidase staining reliably reveals the complete innervation of full-thickness whole mounts of hollow organs and thick sections of central nervous tissue. The method has several advantages. The resin-embedded tissue does not degrade; the immunostaining is non-fading and permanent and neurochemically defined features can be mapped at large scale without confocal microscopy.

Unusually intense 18F‐fluorodeoxyglucose (FDG) uptake by a mature ovarian teratoma: A pitfall of FDG positron emission tomography

We present a 32-year-old woman with an ovarian tumor. A large ovarian tumor with solid components was detected by ultrasonography and magnetic resonance imaging. Contrast enhanced magnetic resonance imaging showed strong enhancement within the solid component. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography was performed for further evaluation and intense FDG uptake into the solid component was observed with standardized uptake values of 12.8 in the early phase and 14.8 in the delayed phase. Therefore, we could not rule out the possibility of a malignant ovarian tumor, and the patient underwent unilateral salpingo-oophorectomy through laparotomy. The tumor was pathologically diagnosed as a mature teratoma with no malignant elements. Histological examination revealed the solid component to be composed mainly of central nervous tissue, which was most likely to be responsible for the intense FDG uptake.

Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue

Scar tissue at sites of traumatic injury in the adult central nervous system presents a combined physical and molecular impediment to axon regeneration. Of multiple known central nervous system scar associated axon growth inhibitors, semaphorin 3A has been shown to be strongly expressed by invading leptomeningeal fibroblasts. We have previously demonstrated that infusion of the small leucine-rich proteoglycan decorin results in major suppression of several growth inhibitory chondroitin sulphate proteoglycans and growth of adult sensory axons across acute spinal cord injuries. Furthermore, decorin treatment of leptomeningeal fibroblasts significantly increases their ability to support neurite growth of co-cultured adult dorsal root ganglion neurons. In the present study we show that decorin has the ability to suppress semaphorin 3A expression within adult rat cerebral cortex scar tissue and in primary leptomeningeal fibroblasts in vitro. Infusion of decorin core protein for eight days resulted in a significant reduction of semaphorin 3A messenger RNA expression within injury sites compared with saline-treated control animals. Both in situ hybridization and immunostaining confirmed that semaphorin 3A messenger RNA expression and protein levels are significantly reduced in decorin-treated animals. Similarly, decorin treatment decreased the expression of semaphorin 3A messenger RNA in cultured rat leptomeningeal fibroblasts compared with untreated cells. Mechanistic studies revealed that decorin-mediated suppression of semaphorin 3A critically depends on erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 function. Collectively, our studies show that in addition to suppressing the levels of inhibitory chondroitin sulphate proteoglycans, decorin has the ability to suppress semaphorin 3A in the injured central nervous system. Our findings provide further evidence for the use of decorin as a potential therapy for promoting axonal growth and repair in the injured adult mammalian brain and spinal cord.

Changes of mitochondrial ultrastructures and function in central nervous tissue of hens treated with tri-ortho-cresyl phosphate (TOCP)

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus ester, is capable of producing organophosphorus ester-induced delayed neurotoxicity (OPIDN) in humans and sensitive animals. The mechanism of OPIDN has not been fully understood. The present study has been designed to evaluate the role of mitochondrial dysfunctions in the development of OPIDN. Adult hens were treated with 750 mg/kg·bw TOCP by gavage and control hens were given an equivalent volume of corn oil. On day 1, 5, 15, 21 post-dosing, respectively, hens were anesthetized by intraperitoneal injection of sodium pentobarbital and perfused with 4% paraformaldehyde. The cerebral cortex cinerea and the ventral horn of lumbar spinal cord were dissected for electron microscopy. Another batch of hens were randomly divided into three experimental groups and control group. Hens in experimental groups were, respectively, given 185, 375, 750 mg/kg·bw TOCP orally and control group received solvent. After 1, 5, 15, 21 days of administration, they were sacrificed and the cerebrum and spinal cord dissected for the determination of the mitochondrial permeability transition (MPT), membrane potential (Δψ(m)) and the activity of succinate dehydrogenase. Structural changes of mitochondria were observed in hens' nervous tissues, including vacuolation and fission, which increased with time post-dosing. MPT was increased in both the cerebrum and spinal cord, with the most noticeable increase in the spinal cord. Δψ(m) was decreased in both the cerebrum and spinal cord, although there was no significant difference in the three treated groups and control group. The activity of mitochondrial succinate dehydrogenase assayed by methyl thiazolyl tetrazolium (MTT) reduction also confirmed mitochondrial dysfunctions following development of OPIDN. The results suggested mitochondrial dysfunction might partly account for the development of OPIDN induced by TOCP.