curcumin and Demyelinating-Diseases

Oxidative stress has been shown to play an important role in the pathogenesis of multiple sclerosis (MS). Curcumin (CUR), an antioxidant compound, can be a potent treatment for neurodegenerative diseases, such as MS. CUR has poor bioavailability; therefore, it is used in nanoforms to increase its bioavailability. In the present study, the effects of CUR and conjugated linoleic acid-CUR (Lino-CUR) on spatial memory and oxidative stress in a putative animal model of MS were investigated. Forty-nine adult male Wistar rats (250 ± 50 g) were randomly divided into seven groups (n = 7): control, sham, ethidium bromide (EB), CUR (20 and 40 μg/kg) + EB, and Lino-CUR (20 and 40 μg/kg) + EB groups. Following MS induction, the groups were treated for 5 consecutive days. Finally, spatial memory and levels of oxidative stress parameters were assessed. Treatment with CUR and Lino-CUR at two doses significantly improved spatial memory and reduced oxidative stress parameters in the experimental models of MS. Furthermore, the effects of high dose (40 μg/kg) of Lino-CUR were more remarkable. These findings suggest that the microinjection of CUR in its synthetic form Lino-CUR significantly ameliorated spatial memory, through the reduction of oxidative stress markers in the brain of studied animals as a rat model of MS.

Topics: Animals; Cognitive Dysfunction; Curcumin; Demyelinating Diseases; Enzyme Inhibitors; Ethidium; Linoleic Acids, Conjugated; Male; Oxidative Stress; Rats; Rats, Wistar

Multiple sclerosis (MS) is an autoimmune disease, associated with central nervous system (CNS) inflammation, demyelination, and axonal loss. Myelin, a multilayer membranous that covers nerve fibers, is essential for rapid impulse conduction. Oligodendrocytes that are generated either from CNS-resident oligodendrocyte progenitor cells (OPCs) or subventricular zone-derived neural stem cells (NSCs) are the myelinating cells of the CNS. The adult CNS maintains a certain endogenous potential to repair myelin damage. However, this process often fails as MS progresses. The origin of this failure is not fully understood, but it is likely to relate to progenitors/stem cells' arrestment in a quiescent state, incapable of generating new oligodendrocyte. Current treatments for MS are immunomodulatory or immunosuppressive medications, with little to no effect on myelin restoration. Recent studies have provided proof-of-principle that CNS remyelination can be promoted either via enhancing endogenous remyelination or by transplanting myelinating cells. Curcumin, a natural polyphenolic compound, has been shown to have therapeutic properties in several neurodegenerative diseases. Here, we investigated the effect of a curcumin nanoformulation, dendrosomal nanoparticles (DNC) on oligodendrogenesis and remyelination, both in vitro and in animal model of demyelination. We indicated that DNC enhanced oligodendrogenesis from NSCs and OPCs, in vitro in dose dependent manner. DNC also induced in vivo remyelination via promotion of oligodendrogenesis. Furthermore, DNC enhanced remyelination capacity of transplanted NSCs through promoting their survival and oligodendrogenesis capacity. Our findings suggest that DNC has significant beneficial effects in demyelinating conditions, either as mono-therapy or as being paired with transplantation approaches.

Topics: Acute Disease; Animals; Astrocytes; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Cuprizone; Curcumin; Demyelinating Diseases; Disease Models, Animal; Embryo, Mammalian; Male; Mice, Inbred C57BL; Nanoparticles; Neural Stem Cells; Neurogenesis; Oligodendroglia; Remyelination

Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context.

Topics: Animals; Anti-Inflammatory Agents; Corpus Callosum; Curcumin; Demyelinating Diseases; Disease Models, Animal; Drug Delivery Systems; Inflammation; Lysophosphatidylcholines; Male; Myelin Sheath; Nanoparticles; Neuroglia; Rats, Wistar

Recent studies have demonstrated that curcumin (Cur) has antioxidant, anti-inflammatory and anti-fibrotic effects. Ethidium bromide (EB) injections into the central nervous system (CNS) are known to induce local oligodendroglial and astrocytic loss, resulting in primary demyelination and neuroinflammation. Peripheral astrogliosis is seen around the injury site with increased immunoreactivity to glial fibrillary acidic protein (GFAP). This investigation aimed to evaluate the effect of Cur administration on astrocytic response following gliotoxic injury. Wistar rats were injected with EB into the cisterna pontis and treated, or not, with Cur (100 mg/kg/day, intraperitoneal route) during the experimental period. Brainstem sections were collected at 15, 21 and 31 days after EB injection and processed for GFAP immunohistochemical staining. Astrocytic reactivity was measured in a computerized system for image analysis. In Cur-treated rats, the GFAP-stained area around the lesion was significantly smaller in all periods after EB injection compared to untreated animals, showing that Cur reduces glial scar development following injury.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Brain Stem; Curcumin; Demyelinating Diseases; Disease Models, Animal; Ethidium; Glial Fibrillary Acidic Protein; Male; Rats; Rats, Wistar; Staining and Labeling

Mutations in MPZ, the gene encoding myelin protein zero (MPZ), the major protein constituent of peripheral myelin, can cause the adult-onset, inherited neuropathy Charcot-Marie-Tooth disease, as well as the more severe, childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3' end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. We examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and we found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. Curcumin, a chemical compound derived from the curry spice tumeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. Our findings suggest that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and may potentially have a therapeutic role in treating selected forms of inherited peripheral neuropathies.

Topics: Apoptosis; Curcumin; Demyelinating Diseases; Endoplasmic Reticulum; HeLa Cells; Hereditary Sensory and Motor Neuropathy; Humans; Mutation; Myelin P0 Protein

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

Topics: Adoptive Transfer; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Central Nervous System; Curcumin; Demyelinating Diseases; DNA-Binding Proteins; Encephalomyelitis, Autoimmune, Experimental; Epitopes, T-Lymphocyte; Female; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-12; Janus Kinase 1; Macrophages; Mice; Mice, Inbred Strains; Microglia; Myelin Basic Protein; Phosphorylation; Protein-Tyrosine Kinases; Signal Transduction; Spleen; STAT3 Transcription Factor; STAT4 Transcription Factor; T-Lymphocytes; Trans-Activators; Tyrosine; Vaccination