chondroitin sulfate proteoglycan Dotaz Zobrazit nápovědu
Chondroitin sulfát je glykosaminoglykan obsažený v proteoglykanech mezibuněčné hmoty chrupavky; při osteoartróze se jeho obsah v chrupavce i kvalita snižují. Chondroitin sulfát patří mezi perorální symptomatické pomalu působící léky osteoartrózy (SYSADOA) s prokázanou symptomatickou účinností u osteoartrózy kolenních a kyčelních kloubů a osteoartrózy drobných ručních kloubů. U gonartrózy byl v několika dvojitě slepých studiích prokázán i jeho strukturální efekt, tj. schopnost zpomalovat morfologickou progresi osteoartrózy, částečný strukturální efekt byl zjištěn i u osteoartrózy rukou. Chondroitin sulfát se podává perorálně v dávce 800 mg denně, jeho účinek nastupuje pozvolna v průběhu 4–12 týdnů, proto se doporučuje v úvodu léčby podat dávku dvojnásobnou. K symptomatické úlevě u osteoartrózy se podávají tříměsíční terapeutické cykly jednou až dvakrát ročně, obvykle v době aktivace artrotického procesu, k dosažení strukturálního efektu je však nutná kontinuální, dlouhodobá léčba (2–3 roky). Chondroitin sulfát nemá prakticky žádné lékové interakce, lze jej proto kombinovat s analgetiky i nesteroidními antirevmatiky. Léčba chondroitin sulfátem je bezpečná. Nežádoucí účinky nejsou časté, mohou se vyskytnout mírné zažívací obtíže, exantém aj., jež obvykle nevedou k přerušení léčby. Závažné nežádoucí účinky při léčbě chondroitin sulfátem popsány nebyly. Chondroitin sulfát je v současné době doporučován k léčbě osteoartrózy i mezinárodními autoritami (EULAR, OARSI).
Chondroitin sulfate is a glycosaminoglycan occurring in proteoglycans of the of cartilage matrix; chondroitin sulfate quality and content in the cartilage are reduced in osteoarttiritis. Chondroitin sulfate is an oral agent of the group of symptomatic slow-acting drugs in osteoarthritis (SYSADOA) with proved efficacy in knee, hip and hand osteoarthritis. Several double-blind studies have also found chondroitin sulfate to have a structure modifying effect, i.e. the potential to prevent from the morphological progression of knee osteoarthritis and partly even of hand osteoarthritis. Chondroitin sulfate Is given orally at a dose of 800 mg daily As it has a slow onset of action, taking 4-12 weeks to develop, it is recommended to start the treatment with a double dose. Symptomatic relief in osteoarthritis is obtained in three-month treatment cycles given once or twice a year, as a rule in activated osteoarthritis. Nevertheless, to achieve a structural effect, continuous long-term treatment is needed (2-3 years). Chondroitin sulfate has practically no drug-drug interactions and thus can be combined with analgesics and non-steroidal anti-inflammatory drugs. Chondroitin sulfate is a safe therapy Adverse events such as mild digestive disorders, rash, etc. are infrequent and usually do not cause treatment discontinuation. No serious adverse events have been reported for the treatment with chondroitin sulfate. It is also currently recommended by the international authorities such as the European League Against Rheumatism (EULAR) and the Osteoarthritis Research Society International (OARSI) for use in osteoarthritis.
- Klíčová slova
- pomalu působící léky osteoartrózy, SYSADOA,
- MeSH
- antirevmatika aplikace a dávkování farmakokinetika farmakologie MeSH
- chondroitin sulfáty aplikace a dávkování farmakokinetika farmakologie MeSH
- hodnocení léčiv statistika a číselné údaje MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- osteoartróza farmakoterapie MeSH
- Check Tag
- lidé MeSH
Spinal cord injuries (SCI), for which there are limited effective treatments, result in enduring paralysis and hypoesthesia, in part because of the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic removal of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restored robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we focused on arm and hand function, seeking to highlight and optimize crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to simultaneously reduce and overcome inhibitory CSPGs. Following a 3-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, as well as on precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG-mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time points following SCI, hopefully leading to clinically relevant translational benefits.
- MeSH
- chondroitinasa ABC farmakologie MeSH
- chondroitinsulfát proteoglykany * farmakologie MeSH
- krysa rodu rattus MeSH
- mícha MeSH
- poranění míchy * MeSH
- potkani Sprague-Dawley MeSH
- přední končetina MeSH
- regenerace nervu fyziologie MeSH
- tyrosinfosfatasy receptorového typu, třída 2 MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Perineuronal nets (PNNs) are extracellular matrix structures surrounding neuronal sub-populations throughout the central nervous system, regulating plasticity. Enzymatically removing PNNs successfully enhances plasticity and thus functional recovery, particularly in spinal cord injury models. While PNNs within various brain regions are well studied, much of the composition and associated populations in the spinal cord is yet unknown. We aim to investigate the populations of PNN neurones involved in this functional motor recovery. Immunohistochemistry for choline acetyltransferase (labelling motoneurones), PNNs using Wisteria floribunda agglutinin (WFA) and chondroitin sulphate proteoglycans (CSPGs), including aggrecan, was performed to characterise the molecular heterogeneity of PNNs in rat spinal motoneurones (Mns). CSPG-positive PNNs surrounded ~70-80% of Mns. Using WFA, only ~60% of the CSPG-positive PNNs co-localised with WFA in the spinal Mns, while ~15-30% of Mns showed CSPG-positive but WFA-negative PNNs. Selective labelling revealed that aggrecan encircled ~90% of alpha Mns. The results indicate that (1) aggrecan labels spinal PNNs better than WFA, and (2) there are differences in PNN composition and their associated neuronal populations between the spinal cord and cortex. Insights into the role of PNNs and their molecular heterogeneity in the spinal motor pools could aid in designing targeted strategies to enhance functional recovery post-injury.
- MeSH
- cholin-O-acetyltransferasa metabolismus MeSH
- chondroitinsulfát proteoglykany metabolismus MeSH
- extracelulární matrix - proteiny metabolismus MeSH
- extracelulární matrix metabolismus MeSH
- krysa rodu rattus MeSH
- mícha cytologie metabolismus MeSH
- motorické neurony cytologie metabolismus MeSH
- neuroplasticita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.
- MeSH
- chondroitin sulfáty * MeSH
- extracelulární matrix MeSH
- mozek MeSH
- myši MeSH
- neuroplasticita * MeSH
- stárnutí MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- chondroitin sulfáty analýza MeSH
- dospělí MeSH
- elektroforéza v polyakrylamidovém gelu metody MeSH
- keratansulfát analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- meziobratlová ploténka metabolismus MeSH
- mladiství MeSH
- proteoglykany biosyntéza izolace a purifikace metabolismus MeSH
- senioři MeSH
- techniky tkáňových kultur MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- senioři MeSH
Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.
- MeSH
- Alzheimerova nemoc farmakoterapie etiologie patofyziologie psychologie MeSH
- antigeny imunologie metabolismus fyziologie MeSH
- cílená molekulární terapie MeSH
- extracelulární matrix metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- neurodegenerativní nemoci farmakoterapie etiologie patofyziologie psychologie MeSH
- neuroplasticita MeSH
- neutralizující protilátky terapeutické užití MeSH
- paměť fyziologie MeSH
- potkani Sprague-Dawley MeSH
- proteoglykany imunologie metabolismus fyziologie MeSH
- protilátky aplikace a dávkování MeSH
- reakční čas MeSH
- tauopatie komplikace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Glycosaminoglycans have anti-inflammatory properties and interact with a variety of soluble and membrane-bound molecules. Little is known about their effects on B cells and humoral immune responses. We show that CS but not dextran or other glycosaminoglycans induces a pronounced proliferation of B cells in vitro compared with TLR4 or TLR9 ligands. With the use of inhibitors and KO mice, we demonstrate that this proliferation is mediated by the tyrosine kinases BTK and Syk but independent of CD44. Antibodies against Ig-α or Ig-β completely block CS-induced B cell proliferation. Injection of CS in mice for 4-5 days expands B cells in the spleen and results in a marked increase of CD138(+) cells in the spleen that is dependent on BTK but independent of CD4(+) T cells. Long-term treatment with CS for 14 days also increases CD138(+) cells in the bone marrow. When mice were immunized with APC or collagen and treated with CS for up to 14 days during primary or after secondary immune responses, antigen-specific humoral immune responses and antigen-specific CD138(+) plasma cells in the bone marrow were reduced significantly. These data show that CD138(+) cells, induced by treatment with CS, migrate into the bone marrow and may displace other antigen-specific plasma cells. Overall, CS is able to interfere markedly with primary and fully established humoral immune responses in mice.
- MeSH
- aktivace lymfocytů účinky léků genetika MeSH
- antigeny CD44 genetika imunologie MeSH
- buňky kostní dřeně imunologie MeSH
- chondroitin sulfáty farmakologie MeSH
- humorální imunita účinky léků genetika MeSH
- intracelulární signální peptidy a proteiny genetika imunologie MeSH
- myši inbrední BALB C MeSH
- myši knockoutované MeSH
- myši MeSH
- plazmatické buňky imunologie MeSH
- pohyb buněk účinky léků imunologie MeSH
- proliferace buněk účinky léků MeSH
- syndekan-1 genetika imunologie MeSH
- toll-like receptor 4 genetika imunologie MeSH
- toll-like receptor 9 genetika imunologie MeSH
- tyrosinkinasy genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
