Neuroscience
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Amyloid beta (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Aβ affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Aβ (1-42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization-activated (Ih) channel currents was examined using whole-cell patch-clamp recording. ⋯ The Ih current density was increased and the activation curve was shifted toward less negative potential in the Aβ-treated group as compared to control group. The enhancing effect of Aβ treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi. These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Aβ treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD.
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Numerous studies have indicated dental pulp stem cells (DPSCs) potency to differentiate into several types of cell lineages. Oligodendrocyte lineage transcription factor 2 (OLIG2) plays an important role in the oligodendrogenic pathway. In this study, a tetracycline (Tet)-inducible system expressing OLIG2 gene was transfected into human DPSCs to direct their differentiation toward oligodendrocyte progenitor cells (OPCs). ⋯ Improvement of behavioral symptoms was efficiently observed from the second week to the sixth week post-transplantation. Our findings showed that exogenous expression of the OLIG2 gene by a Tet-regulated system could be used as an efficient way to induce the differentiation of DPSCs into functional oligodendrocytes. Meanwhile, the DPSC-derived OPCs have relevant therapeutic potential in the animal model of sciatic nerve injury and therefore might represent a valuable tool for stem cell-based therapy in inflammatory and degenerative diseases of the peripheral and central nervous systems (CNSs).
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Primary somatosensory cortex (S1) contains a nociceptive map that localizes potential tissue damage on the body and encodes stimulus intensity. An objective and specific biomarker of pain however is currently lacking and is urgently required for use in non-verbal clinical populations as well as in the validation of pre-clinical pain models. Here we describe studies to see if the responses of the S1 in juvenile rats are different to those in the adult. ⋯ Noxious heat evoked a significant increase in theta band (4-8 Hz) activity in adults only (P<0.0001 compared to baseline; P<0.0001 compared to juveniles). There were no significant differences in EEG responses to innocuous thermal stimuli. These data show that there are significant alterations in the processing of nociceptive inputs within the maturing cortex and that cortical theta activity is involved only in the adult cortical response to noxious stimulation.
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Glucose uptake in neurons depends on their cellular/physiological activity and the extracellular concentration of glucose around the cell. High concentration of extra-cellular glucose, as under hyperglycemic conditions or pathological condition in diabetes, may persist for extended periods of time in neurons and trigger cellular damage by altering voltage-gated sodium channels (VGSCs), the exact mechanism of which remains unclear. Therefore, we hypothesized that high glucose may directly affect kinetics of the VGSCs in the dorsal root ganglion (DRG) neurons. ⋯ Steady-state fast inactivation of INa was shifted in the hyperpolarizing direction whereas voltage-dependent activation was shifted in the rightward direction. Diabetic rats treated with lidocaine and tetracaine (3 mg/kg, i.p.) significantly improved thermal hyperalgesia, mechanical allodynia and motor nerve conduction velocity with a significant inhibition of TTX-R INa density as compared to the diabetic control. These results suggest that HG exposure increases the TTX-R Na(+) channel activity sensitive to Na(+) channel blockers, lidocaine and tetracaine.
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Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. ⋯ Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.