curcumin and Charcot-Marie-Tooth-Disease

Hereditary neuropathies are classified into Charcot-Marie-Tooth disease (CMT), familial amyloid polyneuropathy (FAP), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). CMTs are furthermore classified into demyelinating neuropathies (CMT1), axonal neuropathies (CMT2) and intermediate form. Duplication of PMP22 (CMT1A) accounts for about 70% of CMT1 and MFN2 mutations account for 25% of CMT2. Genes involved in phosphoinositide regulation cause CMT4; MTMR2 mutation in CMT 4B1 and MTMR13/SBF2 mutation in CMT4B2. In addition to these genes, FIG4, which is a causative gene of pale tremor mouse, is newly identified as a gene for CMT4J. MFN2 and GDAP1 cause CMT2 or CMT4. These genes regulate mitochondrial fusion and fission. Altered axonal mitochondrial transport is suggested as the pathogenesis of the CMT. In animal model with pmp22 duplication, ascorbic acid seems to be effective to prevent disease progression. Nationwide trial of ascorbic acid therapy for CMT1A is now ongoing by the intractable neuropathy study group. Curcumin treatment educes apoptosis of cells that express PMP22 point mutation and partially mitigates the severe neuropathy phenotype of Trembler-J mouse model in a dose-dependent manner. Curcumin treatment may have a potential therapeutic role in CMT with PMP22 point mutation in humans. The high throughput system of diagnosis for CMT has been developed by employing a resequencing array system.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Curcumin; Humans; Mice; Myelin Proteins; Oligonucleotide Array Sequence Analysis; Point Mutation

Topics: Animals; Cell Culture Techniques; Charcot-Marie-Tooth Disease; Curcumin; Ethanol; Mammals; Mice; Myelin Proteins

The most prevalent form of Charcot-Marie-Tooth disease (CMT type 1A) is characterized by duplication of the PMP22 gene, peripheral dysmyelination and decreased nerve conduction velocities leading to muscle weakness. Recently, oxidative stress was reported as a feature in CMT1A patients. Curcumin exhibits antioxidant activities and has shown beneficial properties on peripheral nerves. However, curcumin presents unfavorable pharmacokinetics. We developed curcumin-cyclodextrin/cellulose nanocrystals (Nano-Cur) to bypass this limitation. The present study investigated the therapeutic potential of Nano-Cur in vitro in Schwann cells (SCs) and in vivo in the transgenic CMT1A rat model. In vitro, Nano-Cur treatment (0.01 μM for 8 h) reduced reactive oxygen species and improved mitochondrial membrane potential in CMT1A SCs. Moreover, Nano-Cur treatment (0.01 μM for 1 week) increased the expression of myelin basic protein in SC/neuron co-cultures. Preliminary in vivo experiments carried out in WT rats showed that intraperitoneal (i.p.) injection of Nano-Cur treatment containing 0.2 mg/kg of curcumin strongly enhanced the bioavailability of curcumin. Afterwards, in 1-month-old male CMT1A rats, Nano-Cur treatment (0.2 mg/kg/day, i.p. for 8 weeks) significantly improved sensori-motor functions (grip strength, balance performance, and mechanical and thermal sensitivities). Importantly, sensory and motor nerve conduction velocities were improved. Further histological and biochemical analyses indicated that myelin sheath thickness and myelin protein expression (myelin protein zero and PMP22) were increased. In addition, oxidative stress markers were decreased in the sciatic nerve and gastrocnemius muscle. Finally, Nrf2 expression and some major antioxidant enzymes were increased in sciatic nerve. Therefore, Nano-Cur significantly improved cellular, electrophysiological, and functional features of CMT1A rats.

Topics: Animals; Cellulose; Charcot-Marie-Tooth Disease; Curcumin; Cyclodextrins; Humans; Male; Nanoparticles; Oxidative Stress; Phenotype; Rats; Rats, Transgenic

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Differentiation; Charcot-Marie-Tooth Disease; Curcumin; Humans; Myelin P0 Protein; Schwann Cells

Charcot-Marie-Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)-transcription factors that inhibit myelination when overexpressed-was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation.

Topics: Action Potentials; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Cell Differentiation; Cells, Cultured; Charcot-Marie-Tooth Disease; Chlorocebus aethiops; COS Cells; Curcumin; Cysteine; Disease Models, Animal; DNA-Binding Proteins; Early Growth Response Protein 2; Electric Stimulation; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Mice; Mice, Transgenic; Motor Activity; Muscle Strength; Mutation; Myelin P0 Protein; Neuromuscular Junction; Octamer Transcription Factor-6; Protein Folding; Proto-Oncogene Proteins c-jun; Regulatory Factor X Transcription Factors; Rotarod Performance Test; Schwann Cells; Transcription Factors; Transfection; X-Box Binding Protein 1