18 research outputs found
New basis of the neurotrophic action of vitamin B12
No full textOver the last few years we have reproduced all of the key morphological and biochemical features of human subacute combined degeneration in the central nervous system and peripheral nervous system of rats made cobalamin-deficient by means of total gastrectomy or a chronic cobalamin-deficient diet. We have also recently clarified the pathogenesis of experimental subacute combined degeneration induced in the rat by cobalamin deprivation. The results of our studies strongly support the notion that cobalamin plays a pivotal role in regulating the balance of the network of cytokines and growth factors in the central nervous system of the rat. We have demonstrated that cobalamin tightly regulates the central nervous system synthesis and/or the cerebrospinal fluid level of two cytokines, tumor necrosis factor-alpha and interleukin-6, and a growth factor, epidermal growth factor. Of these neuroactive agents, one, tumor necrosis factor-alpha, is neurotoxic, whereas the others are neurotrophic. Therefore, it becomes clear that cobalamin-deficient central neuropathy is caused not by the withdrawal of the vitamin, but reflects a locally increased production of neurotoxic agents, combined with the locally decreased production of neurotrophic agents
Different patterns of expression of ornithine decarboxylase mRNAs in rat liver after acute administration of hepatocarcinogens
No full textIn the present study, we have evaluated the induction of ornithine decarboxylase (ODC) activity in rat liver after acute in vivo administration of different hepatocarcinogens, and correlated the ODC activity peaks with the accumulation of the three ODC-related mRNA species in rat liver at different times after the intraperitoneal injection of different hepatocarcinogens. ODC activity peaked 16 h after 2-acetylaminofluorene (2-AAF) treatment, while accumulation of the three ODC-mRNAs, starting 4 h after the injection, was maximal 6 h later. Thioacetamide (TAA) administration caused a single peak of ODC activity 20 h after treatment, while there had been the maximum increases of the three ODC-mRNAs 4-h earlier. The first ODC activity peak occurred 20 h after treatment with 3'-methyl-4-(dimethylamino)azobenzene (MDAB), at the same time that accumulation of the ODC-mRNAs was maximum. There was no increase in ODC-mRNA accumulation at 28 h or 36 h after MDAB treatment, the time at which ODC activity once again peaked. All the ODC-related transcripts accumulated after MDAB treatment, although to different degrees. The 1.7 kilobase (kb) transcript accumulated the most after 2-AAF treatment. After TAA treatment, the 2.2 kb mRNA was the most abundantly expressed. In neonatal liver, in which ODC activity is physiologically high, the 1.7 kb mRNA is expressed more abundantly than the other two ODC-related transcripts. These results demonstrate that the peak of ODC enzyme activity does not always correspond in time with the peak of ODC-mRNA accumulation; that different hepatocarcinogens induce different patterns of accumulation of the ODC-related transcripts; and that the minor ODC-related transcript (1.7 kb) in rat liver seems to be expressed not only constitutively but is also inducible
Cobalamin (vitamin B12) positively regulates interleukin-6 levels in rat cerebrospinal fluid
No full textWe have previously demonstrated that the repeated intracerebroventricular (i.c.v.) microinjection of interleukin-6 (IL-6) prevented the myelinolytic lesions of cobalamin-deficient (Cbl-D) central neuropathy [or subacute combined degeneration (SCD)] in totally gastrectomized (TGX) rats. We therefore hypothesized that cobalamin (Cbl) may actually regulate IL-6 levels in rat cerebrospinal fluid (CSF). We measured IL-6 levels in the CSF of rats made Cbl-D by means of total gastrectomy (TG) or chronic feeding with a Cbl-D diet and killed at different times from the beginning of the experiment, and found that IL-6 levels significantly and progressively decreased over time. Chronic 2-month Cbl administration started 1 week after surgery prevented the decrease in IL-6 levels and, when it was started 2 months after surgery, it significantly increased IL-6 levels, but not to presurgical values. We also investigated whether IL-6 decrease might be ultimately due to the Cbl-deficiency-linked decrease in epidermal growth factor (EGF) synthesis. Repeated i.c.v. administrations of EGF to TGX rats did not modify CSF IL-6 levels. These results, together with those of a previous study showing the preventive effect of IL-6 treatment on SCD lesions, demonstrate that: (i) Cbl selectively regulates CSF IL-6 levels; and (ii) decreased IL-6 availability plays a role in the pathogenesis of the experimental SCD, in which no evidence of inflammatory and/or immunological reaction has been observed
Circular RNAs: Emblematic Players of Neurogenesis and Neurodegeneration
No full textIn the fascinating landscape of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are peeping out as a new promising and appreciated class of molecules with great potential as diagnostic and prognostic biomarkers. They come from circularization of single-stranded RNA molecules covalently closed and generated through alternative mRNA splicing. Dismissed for many years, similar to aberrant splicing by-products, nowadays, their role has been regained. They are able to regulate the expression of linear mRNA transcripts at different levels acting as miRNA sponges, interacting with ribonucleoproteins or exerting a control on gene expression. On the other hand, being extremely conserved across phyla and stable, cell and tissue specific, mostly abundant than the linear RNAs, it is not surprising that they should have critical biological functions. Curiously, circRNAs are particularly expressed in brain and they build up during aging and age-related diseases. These extraordinary peculiarities make circRNAs potentially suitable as promising molecular biomarkers, especially of aging and neurodegenerative diseases. This review aims to explore new evidence on circRNAs, emphasizing their role in aging and pathogenesis of major neurodegenerative disorders, Alzheimer’s disease, frontotemporal dementia, and Parkinson’s diseases with a look toward their potential usefulness in biomarker searching
Methylmalonic acid as a marker for cobalamin deficiency: fact or fantasy? Elucidations from the cobalamin-deficient rat
No full textThe Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis
No full textAlzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes
Different uptake of cobalamin (vitamin B12) by astrocytes and oligodendrocytes isolated from rat spinal cord
No full textIn the present study, we hypothesized that cobalamin (Cbl) deficiency might affect astrocytes and oligodendrocytes of rat spinal cord (SC) differently. Radiolabeled Cbl ([Cyano-14C]cyano-Cbl) was used to investigate whether the in vitro uptake of Cbl is different in primary cultures of oligodendrocytes and astrocytes. In culture medium supplemented with serum that naturally contains Cbl, the time course of labeled Cbl uptake by neonatal oligodendrocytes had two peaks, at 8 h and 24 h. No uptake was observed when the same cells were cultured in a serum-free medium and consequently in the absence of Cbl. Oligodendrocytes isolated from adult rat SC showed no uptake under any of the tested conditions. Astrocytes isolated from adult Cbl-deficient and newborn rat SC, both cultured in a medium supplemented with serum, showed peak Cbl uptake at 8 h and 12 h, respectively, whereas those isolated from the SC of an adult normal rat cultured under the same conditions showed no uptake throughout the experimental period. Astrocytes isolated from normal, Cbl-deficient adult rats and newborns cultured in a serum-free medium not containing Cbl, showed a similar trend of Cbl uptake with a peak at 24 h. Oligodendrocytes isolated from Cbl-deficient rats showed no uptake when cultured in medium with or without serum. This study provides evidence for a difference in the uptake of labeled Cbl between rat SC astrocytes and oligodendrocytes in relation to (1) age of the donor SC, (2) Cbl status of the donor SC, and (3) Cbl deficiency in the incubation medium that facilitates Cbl uptake in neonatal and adult astrocytes
Extracellular Vesicles in Multiple Sclerosis: Role in the Pathogenesis and Potential Usefulness as Biomarkers and Therapeutic Tools
No full textAlthough extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs’ involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers
Cobalamin (vitamin B12)-deficiency-induced changes in the proteome of rat cerebrospinal fluid
No full textWe studied the changes in the proteome of CSF (cerebrospinal fluid) in two animal models of Cbl (cobalamin) deficiency: TGX (totally gastrectomized) rats and rats fed a Cbl-D (Cbl-deficient) diet. Two-dimensional PAGE was used to detect qualitative and quantitative variations in proteins in the CSF samples. The peak increase in total CSF protein concentration was observed 4 months after TG (total gastrectomy) and after 6 months of eating a Cbl-D diet. There is a specific increase 4 months after TG in the spots corresponding to alpha1-antitrypsin and the de novo presence of thiostatin and haptoglobin beta. Cbl-replacement treatment in 4-month-TGX rats corrected these alterations in the CSF proteome. However, most of the CSF proteome alterations attenuated in Cbl-untreated 8-month-TGX rats and in rats fed a Cbl-D diet for 16 months. Transthyretin concentration varied slightly in the CSF of both types of Cbl-D rat, whereas the relative abundance of prostaglandin D synthase rose sharply in the CSF of the rats fed a Cbl-D diet for 16 months. We have demonstrated previously that the histological and ultrastructural CNS (central nervous system) damage in both types of Cbl-D rat appears within 2-3 months of Cbl deficiency, and thus appears to precede the alterations in the CSF proteome. The CSF proteome patterns of rats in which phlogosis was induced in or outside the CNS are quite different from those of the CSF of Cbl-D rats. All these findings demonstrate that the alterations in the CSF proteome of Cbl-D rats are specifically linked to Cbl deficiency
