Due to the structural similarity to N-methyl-4-phenyl pyridinium (MPP + ), paraquat might induce dopaminergic toxicity in the brain. However, its blood-brain barrier (BBB) penetration has not been well documented. We studied the manner of BBB penetration and neural cell uptake of paraquat using a brain microdialysis technique with the HPLC/UV detection in rats. After subcutaneous administration, paraquat appeared dose-dependently in the dialysate. In contrast, MPP + could not penetrate the BBB in either control or paraquat pre-treated rats. These data indicated that the penetration of paraquat into the brain would be mediated by a specific carrier process, not resulting from the destruction of the BBB function by paraquat itself or a paraquat radical. To examine whether paraquat was carried across the BBB by a certain amino acid transporter, L-valine or L-lysine was pre-administered as a co-substrate. The pre-treatment of L-valine, which is a high affinity substrate for the neutral amino acid transporter, markedly reduced the BBB penetration of paraquat. When paraquat was administered to the striatum through a microdialysis probe, a significant amount of paraquat was detected in the striatal cells after a sequential 180-min washout with Ringer's solution. This uptake was significantly inhibited by a low Na + condition, but not by treatment with putrescine, a potent uptake inhibitor of paraquat into lung tissue. These findings indicated that paraquat is possibly taken up into the brain by the neutral amino acid transport system, then transported into striatal, possibly neuronal, cells in a Na + -dependent manner.Theme: DISORDERS OF THE NERVOUS SYSTEM Topic: Neurotoxicity
Higher education for sustainable development (HEfSD) is being significantly shaped by the global sustainability agenda. Many higher education institutions, responsible for equipping the next generation of sustainability leaders with knowledge and essential skills, proactively try to action the sustainable development goals (SDGs) in HEfSD policy, curriculum and practice through scattered and isolated initiatives. Yet, these attempts are not strategically supported by a governing approach to HEfSD or coordinated effectively to tackle social and environmental sustainability. These predicaments not only widen the gap between HEfSD policy, curriculum and practice but also exacerbate the complexities between human and environmental interactions compromising overall sustainability. However, these efforts represent a potential for actioning the Global Agenda for Sustainable Development. Based on a qualitative research strategy, theory building methodology and various methodological techniques (surveys, policy and literature review, group and individual interviews), this research suggests that the advancement of HEfSD in policy, curriculum and practice depends largely on a better understanding of existing gaps, target areas, commonalities and differences across regional HEfSD agendas. This will hopefully provide higher education institutions and their stakeholders across regions with some conceptual and practical tools to consider strategically how HEfSD can successfully be integrated into policy, curriculum and practice in alignment with SDGs and with the overall mandate of the Global Agenda for Sustainable Development.
The extracellular domain of the metabotropic glutamate receptor 1alpha (mGluR1alpha) forms a dimer and the ligand, glutamate, induces a structural rearrangement in this domain. However, the conformational change in the cytoplasmic domain, which is critical for mGluR1alpha's interaction with G proteins, remains unclear. Here we investigated the ligand-induced conformational changes in the cytoplasmic domain by fluorescence resonance energy transfer (FRET) analysis of mGluR1alpha labeled with fluorescent protein(s) under total internal reflection field microscopy. Upon ligand binding, the intersubunit FRET efficiency between the second loops increased, whereas that between first loops decreased. In contrast, the intrasubunit FRET did not change clearly. These results show that ligand binding does not change the structure of each subunit, but does change the dimeric allocation of the cytoplasmic regions, which may underlie downstream signaling.
Background and purpose: Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E2 (PGE2) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia. Experimental approach: Toll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO2-Lipid A (KDO2) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE2 and TNF levels were measured by mass spectometry and ELISA. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE2 and TNF. Key results: Spinal administration of LPS and KDO2 produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE2 and TNF. Intrathecal pentoxifylline blunted PGE2 and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE2 induced by LPS and KDO2 was attenuated by i.t. administration of ketorolac. Conclusions and implications: Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia.
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