acyclovir and Alzheimer-Disease

We report a case of zona ophthalmica complicated with a complete ophthalmoplegia. In the literature only 19 cases have been reported the last 30 years, with a variety of possible pathophysiological mechanisms. Our patient's mydriasis reacted to diluted pilocarpine 0.125% which is a sign of Adie's pupil and is not supposed to occur in mydriasis caused by a third nerve palsy. We review the literature on the possible pathogenesis of this hypersensitivity.

Topics: Acyclovir; Aged; Alzheimer Disease; Benzimidazoles; Drug Hypersensitivity; Drug Therapy, Combination; Female; Herpes Zoster Ophthalmicus; Humans; Hyperthyroidism; Injections, Intravenous; Ophthalmoplegia; Ovarian Neoplasms; Pilocarpine

Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity.. This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease.. Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested.. Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus.. Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Acyclovir; Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antiviral Agents; Butyrylcholinesterase; Donepezil; Humans; Prodrugs; Rats; Scopolamine; Valacyclovir

Alzheimer's Disease (AD) is the sixth leading cause of death in the United States. Recent studies have established a potential link between herpes simplex virus 1 (HSV-1) infection and the development of AD. HSV-1 DNA has been detected in AD amyloid plaques in human brains, and treatment with the antiviral acyclovir (ACV) was reported to block the accumulation of the AD-associated proteins beta-amyloid (Aβ) and hyper-phosphorylated tau (p-tau) in Vero and glioblastoma cells. Our goal was to determine whether the accumulation of AD-related proteins is attributable to acute and/or latent HSV-1 infection in mature hippocampal neurons, a region of the brain severely impacted by AD. Primary adult murine hippocampal neuronal cultures infected with HSV-1, with or without antivirals, were assessed for Aβ and p-tau expression over 7 days postinfection. P-tau expression was transiently elevated in HSV-1-infected neurons, as well as in the presence of antivirals alone. Infected neurons, as well as uninfected neurons treated with antivirals, had a greater accumulation of Aβ

Topics: Acyclovir; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antiviral Agents; Brain; Chlorocebus aethiops; Female; Herpes Simplex; Herpesvirus 1, Human; Hippocampus; Mice; Neurons; Peptide Fragments; Phosphorylation; Plaque, Amyloid; Primary Cell Culture; tau Proteins; Vero Cells; Virus Replication

Alzheimer's disease (AD) is the most common neurodegenerative disease. However, effective drugs for this disease have not yet been developed. The analysis of big data indicated that childhood herpes virus infection may be associated with the incidence of AD, suggesting that anti-herpetic drugs, such as acyclovir, may have preventive and suppressive effects in AD therapy. Moreover, short-term use of dexamethasone (DXMT), a clinical used synthetic corticosteroid, could effectively inhibit AD-related neuroinflammation. In this study, we have found that the combination of acyclovir and DXMT, but not acyclovir or DXMT alone, could protect against AD causing β-amyloid (Aβ) oligomer-induced spatial cognitive impairments. Moreover, acyclovir and DXMT could prevent Aβ oligomer-induced over-activation of microglia and astrocytes, and over-expression of pro-inflammatory cytokines, indicating that anti-AD effects of drug combination might be at least partially via neuroinflammation inhibition and immunomodulation. Furthermore, Aβ oligomer-induced decrease of PSD-95 and increase of pTau expression was prevented by the combination of acyclovir and DXMT, suggesting the involvement of synaptic protective effects of the drug combination. Taken together, our studies indicated that the combination of acyclovir and DXMT might be an alternative therapy for the treatment of AD.

Topics: Acyclovir; Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Cognitive Dysfunction; Dexamethasone; Drug Therapy, Combination; Male; Mice; Microglia; Neuroprotective Agents; Peptide Fragments

Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of β-amyloid (Aβ) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer's disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aβ, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aβ as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aβ and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aβ and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57-1293, which acts by a different mechanism from ACV. We found that BAY 57-1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aβ and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57-1293 than by ACV. These data suggest that BAY 57-1293 would be a more effective agent than ACV for treating AD.

Topics: Acyclovir; Alzheimer Disease; Amyloid beta-Peptides; Antiviral Agents; DNA Helicases; DNA Primase; Down-Regulation; Enzyme Inhibitors; Herpes Simplex; Herpesvirus 1, Human; Humans; Pyridines; Sulfonamides; tau Proteins; Thiazoles; Viral Proteins; Virus Replication

Alzheimer's disease (AD) afflicts around 20 million people worldwide and so there is an urgent need for effective treatment. Our research showing that herpes simplex virus type 1 (HSV1) is a risk factor for AD for the brains of people who possess a specific genetic factor and that the virus causes accumulation of key AD proteins (β-amyloid (Aβ) and abnormally phosphorylated tau (P-tau)), suggests that anti-HSV1 antiviral agents might slow AD progression. However, currently available antiviral agents target HSV1 DNA replication and so might be successful in AD only if Aβ and P-tau accumulation depend on viral DNA replication. Therefore, we investigated firstly the stage(s) of the virus replication cycle required for Aβ and P-tau accumulation, and secondly whether antiviral agents prevent these changes using recombinant strains of HSV1 that progress only partly through the replication cycle and antiviral agents that inhibit HSV1 DNA replication. By quantitative immunocytochemistry we demonstrated that entry, fusion and uncoating of HSV1, are insufficient to induce Aβ and P-tau production. We showed also that none of the "immediate early" viral proteins is directly responsible, and that Aβ and P-tau are produced at a subsequent stage of the HSV1 replication cycle. Importantly, the anti-HSV1 antiviral agents acyclovir, penciclovir and foscarnet reduced Aβ and P-tau accumulation, as well as HSV1, with foscarnet being less effective in each case. P-tau accumulation was found to depend on HSV1 DNA replication, whereas Aβ accumulation was not. The antiviral-induced decrease in Aβ is attributable to the reduced number of new viruses, and hence the reduction in viral spread. Since antiviral agents reduce greatly Aβ and P-tau accumulation in HSV1-infected cells, they would be suitable for treating AD with great advantage unlike current AD therapies, only the virus, not the host cell, would be targeted.

Topics: Acyclovir; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antiviral Agents; Cell Line; Cells, Cultured; Cricetinae; DNA Replication; DNA, Viral; Herpesvirus 1, Human; Humans; Protein Biosynthesis; tau Proteins; Time Factors; Virus Replication