Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

[Protective effect of Forsythiae Fructus extract on mice with herpes simplex encephalitis].

This study aims to explore the protective effect of Forsythiae Fructus extract(FFE) against herpes simplex virus encephalitis(HSE) in mice. To be specific, life extension rate of mice, viral load in mouse brain, levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interferon-α(IFN-α), and nitric oxide(NO) content in mouse brain were determined. Mice were classified into normal group, model group, acyclovir(ACV) group, and high-dose, medium-dose, and low-dose(100, 50, 25 mg·kg~(-1), respectively) FFE groups. HSE was induced in mice in corresponding groups. Then, the life extension rate was compared among groups. Viral load in brain was detected by real-time fluorescent quantitative PCR, the changes of TNF-α, IL-1ß, and IFN-α in brain by enzyme-linked immunosorbent assay(ELISA), NO content in brain with nitrate reduction method, and pathological changes by hematoxylin-eosin(HE) staining. The result showed that the life extension rate in the high-dose, medium-dose, and low-dose FFE groups was 27.93%, 19.94%, and 10.66%, respectively, and the difference between the high-dose group and the model group was statistically significant(P<0.05). FFE decreased the viral load in brains of HSE mice. The levels of TNF-α, IL-1ß, and IFN-α in ACV group and high-dose and medium-dose FFE groups were lower than those in the model group(P<0.01,P<0.05), and NO content in the three FFE groups was lower than that in the model group(P<0.01). In conclusion, FFE can improve the survival rate of HSE mice, reduce the load of herpes simplex virus type Ⅰ(HSV-1) in the brains of HSE mice, decrease the levels of inflammatory factors and NO content, and alleviate inflammation and pathological damage, thereby protecting the central nervous system.

[Improved instrumental activities of daily living in acquired savant syndrome patient after developing interest in drawing].

We performed examinations of a 73-year-old, right-handed man who developed herpes simplex encephalitis, with cognitive dysfunction including severe Wernicke's aphasia. Although he had never previously been interested in arts, use of a coloring book, recommended by his wife, led him to start drawing. A few years after the onset of brain disease, the patient began to copy pictures of landscapes. The lesion was in the left hemisphere and his work showed a strongly realistic tendency, thus we think that this case demonstrated characteristics of acquired savant syndrome. Along with the increase in drawing ability, instrumental activities of daily living (IADL), such as shopping and use of public transport, were also considerably improved in this patient. On the other hand, results of neuropsychological tests, such as the Standard Language Test of Aphasia, were not improved. We concluded that a sense of accomplishment from the drawing activity and communication with supporters might have led to improvement of IADL in this case.

Haloperidol discontinuation in a herpes simplex encephalitis patient with atypical abnormal movements using the herbal medicine Ukgansan-gami: A case report.

Recently, the herbal medicine Ukgansan (Yigansan in China, Yokukansan in Japan) was reported to be effective in the management of movement disorders. We report the case of a 62-year-old woman with herpes simplex encephalitis exhibiting atypical abnormal movements in the chronic stage. While controlling the abnormal movements with haloperidol, an antipsychotic agent, we prescribed Ukgansan-gami, an extract of a variant of Ukgansan, at a dose of 12 g/day to prevent the recurrence of abnormal movements and allow for the discontinuation of haloperidol. The patient was successfully treated with Ukgansan-gami, with no further recurrence of symptoms, making the use of haloperidol no longer necessary. The potential mechanism of action of Ukgansan involves the inhibition of nervous system hyperexcitability through the suppression of glutamate sodium channels, as well as attenuation of hypermotility through serotonin regulation. The present case suggests that herbal medicine therapy was likely to be an alternative to antipsychotics.

Acute retinal necrosis in a patient with remote severe herpes simplex encephalitis.

A 60-year-old man with a history of severe herpes simplex virus type 1 (HSV-1) encephalitis 2 years prior presented with acute onset of visual loss in the left eye. Dilated funduscopic examination showed retinitis and occlusive vasculitis with retinal necrosis. PCR of the vitreous fluid was positive for HSV-1, and he was diagnosed with acute retinal necrosis (ARN) due to HSV-1. The patient was treated with intravenous acyclovir and intravitreous foscarnet for 2 weeks, followed by high dose oral valacyclovir for 2 weeks. He was subsequently placed on planned life-long suppressive valacyclovir. His case demonstrates that acute visual loss concomitant with or subsequent to HSV-1 encephalitis warrants suspicion of ARN. Prompt therapy with effective antiviral medication is necessary to reduce the risk of sight-threatening complications. Chronic suppression with oral antiviral therapy after ARN is recommended to prevent involvement of the contralateral eye, though there is no consensus on the duration and dosage of antivirals.

Efficacy of acyclovir for herpes simplex encephalitis: A protocol for a systematic review of randomized controlled trial.

BACKGROUND: Clinical researches indicate that acyclovir can be used to herpes simplex encephalitis (HSE). However, no systematic review has explored its efficacy for the treatment of HSE. Therefore, this study systematically will investigate the efficacy and safety of acyclovir for patients with HSE. METHODS: We will search the following databases from inceptions to March 1, 2019 without any language restrictions: Cochrane Library, Embase, MEDICINE, PsycINFO, Web of Science, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. This study will include randomized controlled trials that assess the efficacy and safety of acyclovir for patients with HSE. Two authors will independently carry out the study selection, data extraction, and risk of bias assessment. Cochrane risk of bias tool will be used to assess the risk of bias assessment. RESULTS: This study will systematically assess the efficacy and safety of acyclovir for HSE. The primary outcome is mortality rate, which is measured by Glasgow coma score, or other instruments. The secondary outcomes include quality of life, as assessed by 36-Item Short Form Health Survey or relevant scales; overall survival, the number of patient who died; the number of patient who had severe sequelae, and adverse events. CONCLUSIONS: The findings of this study may provide the existing evidence on the efficacy and safety of acyclovir for HSE. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019125999.

Herpes simplex encephalitis with thalamic, brainstem and cerebellar involvement.

Herpes simplex virus encephalitis is a common and treatable cause of acute encephalitis in all age groups. Certain radiological features such as temporal parenchymal involvement facilitate the diagnosis. The use of herpes simplex virus polymerase chain reaction has expanded the clinical and imaging spectrum. We report the case of a young patient who presented with a movement disorder and predominant involvement of thalami, brainstem and cerebellum on magnetic resonance imaging, and was diagnosed with herpes simplex virus encephalitis. Differentiation from Japanese encephalitis may be difficult in these patients, especially in endemic areas, and may necessitate the use of relevant investigations in all patients.

[Diagnostic and therapeutic strategy for acyclovir-resistant herpes encephalitis].

Acyclovir (ACV), which inhibits the replication of herpes simplex virus, is the standard drug for the treatment of herpes simplex encephalitis. Thanks to the introduction of ACV, the morbidity and mortality of HSE patients have significantly improved. However, the disease is still the severe infection, because it makes some patients with HSE suffer from severe consequences. The sensitivity test of the etiological HSV to ACV is very difficult due to the inability of isolation of the virus from cerebrospinal fluid (CSF). The cases of the ACV treatment-resistant HSE patients have been reported. However, these cases were not virologically confirmed. The first case of encephalitis in newborn baby with HSE caused by an ACV-resistant HSV-1, which was virologically confirmed, was reported by our group. According to the sensitivity profile of the causative viruses to antiviral drugs, the drugs of choice for HSE should be properly considered. Strategy for diagnoses of HSE including antiviral sensitivity assessment and selection of drugs in HSE is reviewed.

Herpes simplex virus encephalitis involving the right thalamus.

Herpes simplex virus (HSV) encephalitis is a rare but often fatal disease if left untreated. A 50-year-old woman was admitted with lethargy, confusion, dysphasia and cough. MRI brain demonstrated bilateral temporal and perisylvian hyperintense signal abnormality extending into the cingulate gyrus, typical of HSV encephalitis. However, there was also signal abnormality involving the right thalamus, indicating thalamic involvement. EEG and cerebrospinal fluid PCR confirmed HSV encephalitis. The patient was started on intravenous acyclovir resulting in marked improvement. Adequate assessment and prompt treatment of HSV encephalitis will aid in achieving adequate recovery. Radiological investigation plays a crucial role in diagnosis with typical MR features a useful aid to diagnosis. HSV encephalitis classically involves the medial temporal lobes, insula and cingulated gyri. The basal ganglia and thalami are nearly always spared. We present a very rare case of HSV encephalitis which involved the right thalamus.

The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis.

The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-α) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 × 104 plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 µg/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-α inhibitor, to improve prognosis of HSE.

Protective activity of the ethanol extract of Cynanchum paniculatum (BUNGE) Kitagawa on treating herpes simplex encephalitis.

To date there has been no valid treatment for herpes simplex encephalitis (HSV). This study explores the protective activity of ethanol extract of Cynanchum paniculatum (bunge) kitagawa for treatment of HSV. Cell models and animal models were established and divided into 4 groups: normal group, virus group, cynanchum paniculatum group and Dexamethasone group. Flow cytometry was employed to detect apoptosis of cell model and TUNEL assay was chosen to detect apoptosis of animal tissues. The survival time of the animal models was observed. ELISA was used to measure TNF-alpha expression and the Greiss method to measure Nitric Oxide (NO) expression in the mouse brain. As a result, it was found that extract of Cynanchum paniculatum can improve the survival rate of HSV-infected mice. The extract could prevent apoptosis in the neuron cell model and reduce apoptosis rate in brain tissue after HSV infection. With the extract intervention, TNF-alpha and NO levels in brain tissue were significantly decreased in the animal model. In conclusion, the extract of Cynanchum paniculatum can prevent HSV-inducing impairment in the cell and animal model of HSE.

Inducing-apoptotic activity of the ethanol extract of Duchesnea indica Focke on treatment of herpes simplex encephalitis.

This study explores the inducing-apoptotic activity of the ethanol extract of Duchesnea indica Focke on treatment of herpes simplex encephalitis. Cell models were employed and divided into 4 groups: normal group, virus group, Duchesnea indica group and dexamethasone group. Cytopathic effect examination was employed to detect apoptosis of PC-12 and BV-2 cells. ELISA was used to measure TNF-α, IL-1ß, and Greiss method to measure NO secretion. Flow cytometry assay for caspase-3 expressions was performed. As a result, the ethanol extract of Duchesnea indica could protect the neuron cell model from impairment by virus. In the cell model of microglia stimulated by herpes simplex virus (HSV), with the ethanol extract intervention, TNF-α, IL-1ß and NO levels were significantly decreased and cell death of BV-2 cells were markedly increased. The expression level of caspase-3 was notably elevated after the extract intervention. In conclusion, the ethanol extract of Duchesnea indica can reduce HSV-induced inflammatory injury on neuron due to the induction of microglia apoptosis.

Evaluation of auditory brainstem potentials in children with acute Herpes simplex encephalitis.

OBJECTIVE: In this study, auditory brainstem potentials (ABPs) were studied in children with Herpes simplex encephalitis (HSE) to determine the ABP abnormalities in HSE during childhood. We also wished to determine whether or not to use ABP in early diagnosis of HSE. METHOD: The study includes 28 children; eight children with acute HSE, nine with nonspecific encephalitis, and 11 healthy age-matched control subjects. The diagnosis of HSE was confirmed by the demonstration of Herpes simplex virus type 1 in CSF by polymerase chain reaction. Recordings of ABPs were performed by using Nihon Kohden Neuropack 2 device. RESULTS: The study includes eight children (four females and four males) with acute HSE, nine children (five males and four females) with nonspecific encephalitis, and 11 healthy age-matched control subjects (six males and five females). Age ranges of the patients and controls were between six months and 12 years. There was not statistically significant difference between the groups for age and gender (p > .05). There were significant differences in the mean latencies of the wave IV on the right ear and in the mean interpeak latencies (IPLs) of the waves III-V on the right and left ears between the nonspecific encephalitis group and the control group (p < .05). However, there were no statistically significant differences between the HSV and control groups (p > .05). In addition, there was no significant difference between HSV and nonspecific groups (p > .05). CONCLUSIONS: Our findings revealed that there were mild ABP abnormalities in children with nonspecific encephalitis, but no ABP abnormality in patients with HSV encephalitis. However, we think that more extensive and detailed studies should be performed to determine whether or not there were ABP abnormalities in childhood HSV encephalitis.

A case of hypothalamic panhypopituitarism with empty sella syndrome: case report and review of the literature.

Empty sella syndrome is frequently accompanied with pituitary dysfunction. Most of the patients with empty sella syndrome demonstrate primary pituitary or stalk dysfunction and few cases show hypothalamic dysfunction. A 71-year-old man manifested appetite loss, nausea and vomiting with hyponatremia and adrenal insufficiency. Hormonal evaluation and cranial MRI revealed a panhypopituitarism with empty sella. Intriguingly, while the response of ACTH to CRH administration was exaggerated, the response to insulin hypoglycemia was blunted. Serum PRL levels were normal. Further, decreased level of fT4, slightly elevated basal levels of TSH, and delayed response of TSH to TRH administration were observed. These findings strongly suggest that the panhypopituitarism is caused by hypothalamic dysfunction. The presence of autoantibodies to pituitary and cerebrum in the patient's serum implies an autoimmune mechanism as a pathogenesis.

The immune response to herpes simplex virus encephalitis in mice is modulated by dietary vitamin E.

Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic encephalitis in humans. HSE is primarily caused by herpes simplex virus (HSV)-1 infection of the brain. HSE results in increased levels of oxidative stress, including the production of reactive oxygen species, free radicals, and neuroinflammation. The most biologically active form of vitamin E (VE) is alpha-tocopherol (alpha-TOC). In cellular membranes, alpha-TOC prevents lipid peroxidation by scavenging free radicals and functioning as an antioxidant. Supplementation with VE has been shown to decrease immunosenescence, improve immune function, and may be neuroprotective. To determine how VE deficiency and VE supplementation would alter the pathogenesis of HSE, we placed weanling male BALB/cByJ mice on VE-deficient (VE-D), VE-adequate (VE-A), or 10x VE-supplemented diets for 4 wk, and then infected the mice intranasally with HSV-1. VE-D mice had more severe symptoms of encephalitis than VE-A mice, including weight loss, keratitis, hunched posture, and morbidity. VE-D mice had increased cytokine and chemokine expression in the brain and increased viral titers. In contrast, VE supplementation failed to decrease cytokine production and had no effect on viral titer. We demonstrated that adequate levels of VE are important in limiting HSE pathology and that 10x supplementation does not enhance protection.

Voice recognition and the posterior cingulate: an fMRI study of prosopagnosia.

Voices, in addition to faces, enable person identification. Voice recognition has been shown to evoke a distributed network of brain regions that includes, in addition to the superior temporal sulcus (STS), the anterior temporal pole, fusiform face area (FFA), and posterior cingulate gyrus (pCG). Here we report an individual (MS) with acquired prosopagnosia who, despite bilateral damage to much of this network, demonstrates the ability to distinguish voices of several well-known acquaintances from voices of people that he has never heard before. Functional magnetic resonance imaging (fMRI) revealed that, relative to speech-modulated noise, voices rated as familiar and unfamiliar by MS elicited enhanced haemodynamic activity in the left angular gyrus, left posterior STS, and posterior midline brain regions, including the retrosplenial cortex and the dorsal pCG. More interestingly, relative to noise and unfamiliar voices, the familiar voices elicited greater haemodynamic activity in the left angular gyrus and medial parietal regions including the dorsal pCG and precuneus. The findings are consistent with theories implicating the pCG in recognizing people who are personally familiar, and furthermore suggest that the pCG region of the voice identification network is able to make functional contributions to voice recognition even though other areas of the network, namely the anterior temporal poles, FFA, and the right parietal lobe, may be compromised.

Can fever treat epileptic encephalopathies?

PURPOSE: To describe resistant epileptic encephalopathies that significantly improved after an acute febrile episode (FE). METHODS: We reviewed the clinical history of patients with daily pharmacoresistant seizures referred to the Saint-Vincent de Paul Hospital in the last 5 years. Four patients experienced seizure arrest in relation with a febrile episode. RESULTS: The four patients suffered from epileptic encephalopathy. Three were symptomatic, one cryptogenic. They presented spasms and atypical absences, beginning after the age of 1 year. All seizures stopped at the onset of fever, and significant EEG improvement was observed. The seizure-free period ranged from 2 to 24 months. DISCUSSION AND CONCLUSION: The close link between the occurrence of FE and the disappearance of seizures and EEG improvement, contrasting with the previous pharmacoresistance of this epileptic encephalopathy, supports a non fortuitous association. Several mechanisms could explain this phenomenon, including viral etiology, hyperthermia, inflammatory-immune reaction and ACTH release. Better understanding this phenomenon could open new therapeutic perspectives.