Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-␥ (IFN-␥)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-␥ (Mig/CXCL9), and interferon-inducible T cell ␣ chemoattractant (I-TAC/ CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3 ؉ lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3 ؉ lymphocytes was increased in patients with advanced necroinflammation. Conclusion: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB 1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB 1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB 1 agonist AM356 (R-methanandamide). AM374/ AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB 1 -linked MAPK signaling, and (3) were blocked by a selective CB 1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB 1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

The strong association between CXCR3-associated chemokines and fibrosis suggests that they may have promise as noninvasive markers of hepatic fibrosis in a predominantly white HCV genotype 1-infected population.

No abstract

Protein deposition is a common event in age-related neurological diseases that are characterized by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of 55 to 69 kDa increased over several days of treatment with chloroquine, while the protein and message levels of synaptic markers were selectively reduced. Neurons of subfields CA1, CA3, and dentate gyrus accumulated protein deposits recognized by antibodies against paired helical filaments and ubiquitin, and this was accompanied by tubulin fragmentation and deacetylation. The deposition filled the basal pole of pyramidal neurons, encompassing the area of the axon hillock and initial dendritic branching but without causing overt neuronal atrophy. Neurons containing the polar aggregates exhibited severely impaired transport along basal dendrites. Transport capability was also lost along apical dendrites, the opposite direction of deposited material in the basal pole; thus, perpetuating the problem beyond physical blockage must be the associated loss of microtubule integrity. These data indicate that transport failure forms a link between tau deposition and synaptic decline, thus shedding light on how protein aggregation events disrupt synaptic and cognitive functions before the ensuing cellular destruction.