Neuroscience
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Progranulin (PGRN), a multifunctional growth factor, appears to play a role in neurodegenerative diseases accompanied by neuroinflammation. In this study, we investigated the role of PGRN in neuroinflammation, especially in the activation of microglia, by means of experimental traumatic brain injury (TBI) in the cerebral cortex of mice. The expression of GRN mRNA was increased in association with neuroinflammation after TBI. ⋯ Moreover, double-immunostaining between phospho-Smad3 and glial fibrillary acidic protein suggested increased TGFβ1-Smad3 signal mainly by astrocytes. The levels of protein carbonyl groups, which reflect protein oxidation, and laminin immunoreactivity, which is associated with angiogenesis, were also significantly increased in KO mice compared to WT mice. These results suggest that PGRN is produced in CD68-positive microglia and suppresses excessive inflammatory responses related to activated microglia after TBI in mice.
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Approximately 50% of patients who survived after aneurysmal subarachnoid hemorrhage (SAH) have cognitive or neurobehavioral dysfunction. The mechanisms are not known. NR2B, one of the subunits of N-methyl-d-aspartate (NMDA) receptors, has been proved to be an important factor for synapse function and behavior cognition. ⋯ The immunohistochemical staining demonstrated expression of NR2B was present mainly in the neurons in all of the three different regions, such as the cortex, hippocampus, and cerebellum. After Ro 25-6981 intraperitoneal administration, learning deficits induced by SAH was markedly aggravated and clinical behavior scale was also significantly decreased. Our results suggest that NR2B expression is down-regulated in the brain after experimental SAH and NR2B antagonism resulted in augmentation of the development of cognitive dysfunction after SAH.
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The sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) is a critical pathway by which sensory neurons sequester cytosolic Ca(2+) and thereby maintain intracellular Ca(2+) homeostasis. We have previously demonstrated decreased intraluminal endoplasmic reticulum Ca(2+) concentration in traumatized sensory neurons. Here we examine SERCA function in dissociated sensory neurons using Fura-2 fluorometry. ⋯ Injury did not affect SERCA function in large neurons. Repeated depolarization prolonged transient recovery, showing that neuronal activation inhibits SERCA function. These findings suggest that injury-induced loss of SERCA function in small sensory neurons may contribute to the generation of pain following peripheral nerve injury.
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Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. ⋯ SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.
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Neurological deficit following cerebral infarction correlates with not only primary injury, but also secondary neuronal apoptosis in remote loci connected to the infarction. Netrin-1 is crucial for axonal guidance by interacting with its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H (UNC5H). DCC and UNC5H are also dependence receptors inducing cell apoptosis when unbound by netrin-1. ⋯ MCAO resulted in the impaired postural reflex after 8 and 14 days, with decreased NeuN marked neurons and increased TUNEL-positive cells, as well as an up-regulation in the levels of cleaved caspase-3 and UNC5H2 protein in the ipsilateral VPN, without significant change in DCC or netrin-1 expression. By exogenous netrin-1 infusion, the number of neurons was increased in the ipsilateral VPN, and both TUNEL-positive cell number and caspase-3 protein level were reduced, while UNC5H2 expression remained unaffected, simultaneously, the impairment of postural reflex was improved. Taken together, the present study indicates that exogenous netrin-1 could rescue neuron loss by attenuating secondary apoptosis in the ipsilateral VPN after focal cerebral infarction, possibly via its receptor UNC5H2, suggesting that relative insufficiency of endogenous netrin-1 be an underlying mechanism of secondary injury in the VPN post stroke.