Neuromolecular medicine
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Neuromolecular medicine · Jun 2013
Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.
We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). ⋯ Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.
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Neuromolecular medicine · Mar 2013
Comparative StudyFisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity.
Aluminum (Al) is an environmental neurotoxin that affects cerebral functions and causes health complications. However, the role of Al in arbitrating glia homeostasis and pathophysiology remains obscure. Astrocyte, microglia activation (reactive gliosis), and associated inflammatory events play a decisive role in neurodegeneration and may represent a target for treating neurodegenerative disorders. ⋯ Pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, were increased upon AlCl3 administration. AlCl3-induced alterations in the activities of SOD, CAT, GST, AChE and levels of GSH, LPO, activity of AChE, behavioral deficits, histologic aberrations, reactive gliosis, and inflammatory niche were attenuated on treatment with fisetin. Collectively, our results indicate that fisetin exerts neuroprotection against AlCl3-induced brain pathology.
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Neuromolecular medicine · Mar 2013
Case Reports Comparative StudyNovel mutations in cyclin-dependent kinase-like 5 (CDKL5) gene in Indian cases of Rett syndrome.
Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. ⋯ The C-terminal domain is required for cellular localization through protein-protein interaction; any mutations in this domain might alter this function of the protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of atypical Rett syndrome with congenital seizure variant.
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Neuromolecular medicine · Mar 2013
Decreased levels of circulating adiponectin in mild cognitive impairment and Alzheimer's disease.
Adiponectin, an adipocytokine released by the adipose tissue and has important roles in the metabolic regulation and inflammatory control, may play an important roles in the physiopathology of psychiatric and neurodegenerative disorders. The aim of the present work was to evaluate adiponectin serum levels in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) as compared to cognitively healthy elders and to correlate these levels with clinical and cognitive parameters. We further evaluated whether circulating adiponectin levels could predict progression from MCI to Alzheimer's disease upon follow-up. ⋯ Circulating adiponectin levels did not predict cognitive decline in the elderly controls (i.e., progression from normal cognition to MCI) or progression to Alzheimer's disease in subjects with MCI. We conclude that lower levels of adiponectin were associated with cognitive dysfunction, though it did not predict additional cognitive decline and conversion to dementia in this cohort of elderly subjects. Decreased adiponectin may be a surrogate marker of the pathological process in AD, linking clinical comorbidities, inflammation and cognitive dysfunction.
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Neuromolecular medicine · Mar 2013
Comparative StudyActivation of tetrodotoxin-resistant sodium channel NaV1.9 in rat primary sensory neurons contributes to melittin-induced pain behavior.
Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in dorsal root ganglion (DRG) neurons play important roles in pathological pain. We recently reported that melittin, the major toxin of whole bee venom, induced action potential firings in DRG neurons even in the presence of a high concentration (500 nM) of TTX, indicating the contribution of TTX-R sodium channels. This hypothesis is fully investigated in the present study. ⋯ Neither NaV1.8 AS ODN nor NaV1.9 AS ODN affects melittin-induced mechanical hypersensitivity. These results provide previously unknown evidence that upregulation of NaV1.9, but not NaV1.8, in small-sized DRG neurons contributes to melittin-induced heat hypersensitivity. Furthermore, melittin-induced biological effect indicates a potential strategy to study properties of TTX-R sodium channels.