دانلود رایگان مقاله انگلیسی اثرات آسیکلوویر و IVIG بر پیامدهای رفتاری بعد از عفونت HSV1 CNS - هینداوی 2017

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV’s beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms.

4. Discussion

A majority of patients (>60%) surviving HSE suffer neurological disturbances that can include loss of smell (anosmia) and speech (aphasia), anxiety, and learning and memory impairments that can be severe despite antiviral treatment [3, 46]. In contrast, ~70% of neonates surviving HSV1 infection suffer permanent neurological impairment, exhibiting diverse symptoms including motor abnormalities such as hemiparesis and spastic quadriplegia, delayed speech, visual impairment or blindness, recurring seizures, and microencephally [47, 48]. The pathophysiological mechanisms responsible for neurologic dysfunction following HSV1 CNS infection are largely unknown. However, the finding that poor neurological outcomes are highly correlated with delayed ACV treatment has been interpreted as evidence that viral-replication-triggered events are casually involved [2]. We exploited delayed administration of antiviral and/or anti-inflammatory drugs to develop a novel mouse model to facilitate studies to elucidate the mechanisms underlying neurological dysfunction resulting from HSV1 CNS infection. Following bilateral ocular infection, all resistant B6 mice developed HSE symptoms and brainstem inflammation that remarkably were absent in mice unilaterally inoculated with the same dose of virus. Although, currently, we cannot explain this difference in pathogenesis, bilateral inoculation of B6 mice nonetheless allowed us to address the role of CNS inflammation in HSV1-induced neurological deficits.