Estradiol attenuates spinal cord injury-related central pain by decreasing glutamate levels in thalamic VPL nucleus in male rats

Central neuropathic pain (CNP) is a complicated medical problem that involves both the spinal and supraspinal regions of the central nervous system. Estrogen, a neuroprotective agent, has been considered a possible candidate for CNP treatment. In this study, we examined the effects of a single dose of 17β-estradiol on glutamate levels in the ventral posterolateral (VPL) nucleus of the rat thalamus. Furthermore, we determined whether there was a correlation between glutamate levels and neuropathic pain induced by unilateral electrolytic spinothalamic tract (STT) lesion. STT lesioning was performed in male Wistar rats at the T8-T9 vertebrae; rats were then administered 17β-estradiol (4 mg/kg, i.p.) 30 min after injury. Glutamate samples were collected using a microdialysis probe and quantified by high performance liquid chromatography. Mechanical allodynia (MA) and thermal hyperalgesia (TH) thresholds were measured pre-injury and 7, 14, and 28 days post-injury. We found that STT lesion significantly increased glutamate levels in the ipsilateral VPL nucleus 14 and 28 days post-injury; this was accompanied by allodynia and hyperalgesia in the hind paws of the rats. Administering 17β-estradiol to the rats decreased glutamate levels in the ipsilateral VPL nucleus and significantly increased MA and TH thresholds. These results suggest that glutamate in the VPL nucleus of the thalamus is involved in the pathology of neuropathic pain after STT injury; furthermore, 17β-estradiol may attenuate this neuropathic pain by decreasing glutamate levels.     

Illuminating the in vitro effects of Epstein-Barr virus and vitamin D on immune response in multiple sclerosis patients

Journal of NeuroVirology - Given the complexity of immune complex diseases including multiple sclerosis (MS) and the plausible interactions between different risk factors, delineating the interplay...     

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1–C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum‐deprived conditions and enhancement of nerve growth factor (NGF)‐induced neurite outgrowth in PC12 neuronal cells. p‐Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm . Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF‐induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25‐ and 22‐fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3‐kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.     

A novel autosomal recessive GJB2‐associated disorder: Ichthyosis follicularis,bilateral severe sensorineural hearing loss,and punctate palmoplantar keratoderma

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell–cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2‐associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2.     

Effect of low-frequency stimulation on kindling induced changes in rat dentate gyrus: an ultrastructural study

It has been shown that low-frequency stimulation (LFS) can induce anticonvulsant effects. In this study, the effect of different LFS frequencies on kindling induced behavioral and ultrastructural changes was investigated. For induction of kindled seizures in rats, stimulating and recording electrodes were implanted in perforant path and dentate gyrus, respectively. Animals were stimulated in a rapid kindling manner. Different groups of animals received LFS at different frequencies (0.5, 1 and 5 Hz) following kindling stimulations and their effects on kindling rate were determined using behavioral and ultrastructural studies. Kindling stimulations were applied for 7 days. Then, the animals were sacrificed and their dentate gyrus was sampled for ultrastructural studies under electron microscopy. All three used LFS frequencies (0.5, 1 and 5 Hz) had a significant inhibitory effect on kindling rate and decreased afterdischarge duration and the number of stimulations to achieve stage 4 and 5 seizures significantly. In addition, application of LFS prevented the increase in the post-synaptic density and induction of concave synaptic vesicles following kindling. There was no significant change between anticonvulsant effects of LFS at different frequencies. Obtained results show that LFS application can prevent the neuronal hyperexcitability by preventing the ultrastructural changes during kindling and this may be one of the mechanisms of LFS anticonvulsant effects.     

Biochemical activities of acetone extracts of Hyssopus angustifolius

Antioxidant and antihemolytic activities of acetone extracts of Hyssopus angustifolius flowers, leaf and stems were investigated employing different in vitro and ex vivo assay systems. IC50, for 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical-scavenging activity were 239.4 +/- 8.4 microg/mL for flowers, 357.8 +/- 11.1 microg/mL for stems and 182.5 +/- 7.5 microg/mL for leaf. All extracts showed moderate nitric oxide scavenging activity. The leaf extract exhibited better hydrogen peroxide scavenging and Fe2+ chelating activity than the others (IC50 were 261.0 +/- 6.2 microg/mL for hydrogen peroxide and 534.0 +/- 9.9 microg/mL for Fe3+ chelating activity). The extracts exhibited good antioxidant activity in linoleic acid peroxidation system and weak reducing power ability. The leaf extract showed better antihemolytic activity than the flower and stem (IC50 = 65.7 +/- 1.8 microg/mL).     

Syntheses and structure-activity relationships of seven manganese-salen derivatives as anti-amyloidogenic and fibril-destabilizing agents against hen egg-white lysozyme aggregation

Accumulation of intra- and/or extracellular misfolded proteins as amyloid fibrils is a key hallmark in more than 20 amyloid-related diseases. In that respect, blocking or reversing amyloid aggregation via the use of small compounds is considered as two useful approaches in hampering the development of these diseases. In this research, we have studied the ability of different manganese-salen derivatives to inhibit amyloid self-assembly as well as to dissolve amyloid aggregates of hen egg-white lysozyme, as an in vitro model system, with the aim of investigating their structure-activity relationships. By coupling several techniques such as thioflavin T and anilinonaphthalene-8-sulfonic acid fluorescence, congo red absorbance, far-UV circular dichroism, and transmission electron microscopy, we demonstrated that all compounds possessed anti-amyloidogenic activities and were capable of dispersing the fibrillar aggregates. In addition, MTT assay of the treated SK-N-MC cells with the preformed fibrils formed in the presence of compounds at a drug-to-protein molar ratio of 5:1, indicated a significant increase in the viability of cells, compared to the fibrils formed in the absence of each of the compounds. Our spectroscopy, electron microscopy, and cellular studies indicated that EUK-15, with a methoxy group at the para position (group R(5)), had higher activity to either inhibit or disrupt the β-sheet structures relative to other compounds. On the basis of these results, it can be concluded that in addition to aromatic rings of each of the derivatives, the type and position of the side group(s) contribute to lower lysozyme fibril accumulation.