The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post-TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d-amphetamine-induced rotational behavior. Adult male Sprague-Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine-induced rotational behavior was assessed 10 days post-CCI. Fourteen days post-CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V max (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury-related changes in vesicular monoamine transporter or D 2 receptor expression (DRD 2 ) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.

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The increased resistance of the glomerulus as a result of contractile dysfunction of mesangial cells (MCs) is associated with reduction of glomerular filtration rate and development of glomerulosclerosis. Evidences show MCs contraction changes with intracellular Ca(2+) concentration ([Ca(2+)](i)). Here, we explore the mechanism of angiotensin II (AngII)-induced Ca(2+) oscillations and MCs contraction. Primary MCs from 3-month-old and 28-month-old rats were used for detection of Ca(2+) oscillations and MC planar area with confocal microscopy. AngII could induce typical Ca(2+) oscillations and contraction of MCs. This process was abolished by thapsigargin, 2-aminoethoxydiphenyl borate, or 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine, and partially inhibited by ryanodine, but could not be inhibited in the absence of extracellular Ca(2+). Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate (InsP(3)) receptors displayed a strong colocalization, which may contribute to the amplification of Ca(2+) response. MLC(20) phosphorylation and MC planar area were associated with AngII-induced Ca(2+) oscillations. The frequency of Ca(2+) oscillations was dependent on the AngII concentration and correlated with the MCs' contractive extent, which could be attenuated by KN-93. The amplitude reduction of oscillations correlated with the decrease in aging-related contraction. In conclusion, [Ca(2+)](i) response of MCs to AngII is characterized by repetitive spikes through the following repetitive cycles: Ca(2+) release by phospholipase C -InsP(3) pathway, Ca(2+) amplification by Ca(2+)-activated RyRs and Ca(2+) reuptake by the endoplasmic reticulum. MCs contraction can be modulated by oscillations not only in an AngII-induced frequency-dependent mode but also in an aging-related, amplitude-dependent mode.

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Background: LA-NPC can be subtyped by ascending (A; T3-4N0-1), descending (D; T1-2N2-3) and ascending-descending (AD; T3-4N2-3) at diagnosis, depending on the extent of tumor spread. These phenotypes differ by prognoses, but germline and somatic molecular drivers underpinning their tumorigenesis are unknown. We aimed to validate the A and AD subtypes of LA-NPC and investigate for germline variants that are associated with them.