Protective effect of melatonin against methamphetamine-induced attention deficits through miR-181/SIRT1 axis in the prefrontal cortex.

INTRODUCTION: Methamphetamine (METH) is an addictive psychostimulant with deleterious effects on the central nervous system. Chronic use of METH in high doses impairs cognition, attention and executive functions, but the underlying mechanisms are still unclear. Sirtuin 1 (SIRT1) is a post-translational regulator that is downregulated following METH neurotoxicity. Melatonin is a neuroprotective hormone that enhances mitochondrial metabolism. Here, we evaluated the effect of melatonin on METH-induced attention deficits disorder and the involvement of the miR-181/SIRT1 axis in melatonin neuroprotection. METHODS AND RESULTS: METH at a dose of 5 mg/kg was injected for 21 consecutive days. The animals were assigned to receive either melatonin or the vehicle after METH injections. Attention levels were evaluated with abject-based attention test. In the prefrontal cortex, the expression levels of miR-181a-5p, SIRT1, p53 and CCAR2, as well as the mtDNA copy numbers were evaluated using qRT-PCR and western blotting. The outcomes revealed that melatonin treatment following METH injections improved METH-induced attention deficits. METH toxicity can be associated with changes in the miR-181/SIRT1 axis, elevated levels of p53 and COXII, and decreased levels of mtDNA in the prefrontal cortex of adult rats. Interestingly, administration of melatonin can improve the expression of these molecules and reduces the toxic effects of METH. CONCLUSION: Melatonin ameliorated the neurotoxicity of METH in the prefrontal cortex and the miR-181/SIRT1 axis is involve in the protective effects of melatonin. However, melatonin can be potentially administrated to improve attention impairment in METH use disorders.

The role of microRNAs in neurobiology and pathophysiology of the hippocampus.

MicroRNAs (miRNAs) are short non-coding and well-conserved RNAs that are linked to many aspects of development and disorders. MicroRNAs control the expression of genes related to different biological processes and play a prominent role in the harmonious expression of many genes. During neural development of the central nervous system, miRNAs are regulated in time and space. In the mature brain, the dynamic expression of miRNAs continues, highlighting their functional importance in neurons. The hippocampus, as one of the crucial brain structures, is a key component of major functional connections in brain. Gene expression abnormalities in the hippocampus lead to disturbance in neurogenesis, neural maturation and synaptic formation. These disturbances are at the root of several neurological disorders and behavioral deficits, including Alzheimer's disease, epilepsy and schizophrenia. There is strong evidence that abnormalities in miRNAs are contributed in neurodegenerative mechanisms in the hippocampus through imbalanced activity of ion channels, neuronal excitability, synaptic plasticity and neuronal apoptosis. Some miRNAs affect oxidative stress, inflammation, neural differentiation, migration and neurogenesis in the hippocampus. Furthermore, major signaling cascades in neurodegeneration, such as NF-Kß signaling, PI3/Akt signaling and Notch pathway, are closely modulated by miRNAs. These observations, suggest that microRNAs are significant regulators in the complicated network of gene regulation in the hippocampus. In the current review, we focus on the miRNA functional role in the progression of normal development and neurogenesis of the hippocampus. We also consider how miRNAs in the hippocampus are crucial for gene expression mechanisms in pathophysiological pathways.

PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) constitutes a group of neurodegenerative disorders with pronounced iron deposition in the basal ganglia. PANK2 mutations are the most common cause of these disorders. C19orf12 was recently reported as another causative gene. We present phenotypic data and results of screening of PANK2 and C19orf12 in 11 unrelated Iranian NBIA patients. METHODS: Phenotypic data were obtained by neurologic examination, magnetic resonance imaging, and interviews. Mutation screening of PANK2 and C19orf12 was performed by sequencing. RESULTS: PANK2 and C19orf12 mutations were found in 7 and 4 patients, respectively. Phenotypic comparisons suggest that C19orf12 mutations as compared with PANK2 mutations result in a milder disease course. CONCLUSIONS: Mutations in both PANK2 and C19orf12 contributed significantly to NBIA in the Iranian patients. To the best of our knowledge, this is the first genetic analysis reported on a cohort of NBIA patients from the Middle East.

Four novel C20orf54 mutations identified in Brown-Vialetto-Van Laere syndrome patients.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a very rare neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. Its mode of inheritance in affected families has usually been autosomal recessive, although autosomal dominant inheritance and incomplete penetrance have also been reported. Recently, C20orf54 was identified as a causative gene for BVVLS. Twelve different mutations have so far been identified in 10 patients affected with BVVLS or the related disorder Fazio Londe syndrome. Here, results of screening of C20orf54 in three unrelated BVVLS patients are reported. Four novel mutations that affect amino acid changes, p.Asn21Ser, p.Pro220His, p.Ala312Val and p.Gly375Asp, were identified in the patients. The causative nucleotide variations were not observed in 200 control individuals. One of the patients harbored compound heterozygous mutations, but only one mutated allele was observed in each of the two remaining patients.

Pantothenate kinase 2 mutation with eye-of-the-tiger sign on magnetic resonance imaging in three siblings.

BACKGROUND: Pantothenate kinase associated neurodegeneration (PKAN) is the most prevalent type of neurodegeneration with brain iron accumulation (NBIA) disorders characterized by extrapyramidal signs, and 'eye-of-the-tiger' on T2 brain magnetic resonance imaging (MRI) characterized by hypointensity in globus pallidus and a hyperintensity in its core. All PKAN patients have homozygous or compound heterozygous mutation in PANK2 gene. METHODS: Three sibling patients were diagnosed based on clinical presentations especially extrapyramidal signs and brain MRI. The exons and flanking intronic sequences of PANK2 were sequenced from DNA of leukocytes of the affected individuals. RESULTS: All patients were homozygous for c.C1069T, p.R357W in PANK2 gene. This mutation is well conserved in the homologous protein of distally related spices. CONCLUSION: In the current study we identified three siblings affected with PKAN, all of them have mutations in PANK2 gene. In MRI of all patients with PANK2 mutation eye-of-the-tiger sign was apparent.

Four cases of brown-vialetto-van laere syndrome from Iran: Clinical and electrophysiologic findings.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disorder. We report our finding about four patients clinically and electrophysiologically diagnosed as BVVLS and denoted their clinical features with comparison to previous reports. The first symptom was bilateral hearing loss and the onset of other cranial nerves involvement varied between 0-15 years. Our patients represented some rare features like upper motor neuron signs in one patient and two cases interestingly developed some clinical improvement. This is the first report of BVVLS from Iran. Our patients which represent Caucasian population had generally similar features like previously reported cases.