Anti-Viral Activity of Alpha Keto Acids
HSV-1 Infected Cells Treated With N115
In various clinical trials it was demonstrated that sodium pyruvate along with other alpha-keto acids, regulated the synthesis of Nitric Oxide and also protected it from destruction by excess hydrogen Peroxide. The underlying chronic inflammatory process in infections, which induces Nitric Oxide synthesis, needed to kill infecting organisms also produces excess oxygen radicals, which will destroy Nitric Oxide. Infected and noninfected wounds and other irritants has been shown to enhance Nitric Oxide production by alveolar macrophages in rats, which also produces an increased level of oxygen radical that can react directly with Nitric Oxide to produce NO2 and peroxynitrites. Peroxynitrite ion and peroxynitrous acid, formed from the interaction of Nitric Oxide and superoxide anions, specifically hydrogen peroxide, are strong oxidant species that work against Nitric Oxide by inducing single-strand breaks in DNA, increasing the levels of inflammatory mediators by activating NF-kappa B and enhancing replication of infective agents, including viruses. This has been demonstrated in Karposis sarcoma in AIDS patients. Hydrogen peroxide and peroxynitrites are very toxic and disruptive to cell membranes via lipid peroxidation not only leading to cell death, but also dysfunction of many cellular membrane functions, such as transport mechanisms. Their effect can destroy the ability of white blood cells to kill invading microorganisms. Over expression of hydrogen peroxide and peroxynitrite has been shown to destroy immune cells at sites of infection , including CD4 and CD8 cells. Over expression of peroxynitrite has been shown to enhance bacterial and viral replication at infected sites do to peroxynitrites ability to enhance NF-kappa B expression. Peroxynitrites, cause injury through the production of chemokines and contribute to viral pathogenesis and they enhance viral mutations. Excess hydrogen peroxide and peroxynitrites can also react with antimicrobial and antiviral drugs to destroy their ability to kill infections. Damaged or infected wounds produce even higher levels of peroxynitrite, which damages non damaged cells and immune cells and drugs needed to treat the damage. Infections with herpes simplex virus I (HSV-1) induces a persistent nuclear translocation of NF-kappa B, which is dramatically enhanced by hydrogen peroxide and peroxynitrite. The activation of NF-kappa B promotes efficient replication by HSV. In epithelial cells HSV-1 induces NF-kappa B causing persistent activation of NF-kappa B, which is a critical regulator of HSV-1 replication. In AIDs patients, HIV-1 also triggers and activates NF-kappa B and AIDS patients have elevated levels of hydrogen peroxide and peroxynitrite, which contributes to the etiology of AIDS related dementia, persistent immunosuppression and Kaposis sarcoma. Hydrogen peroxide and peroxynitrite have also been shown to be very destructive to CD4 and CD8 cells. We have discovered that alpha-keto acids including sodium pyruvate, can decrease the levels and production of hydrogen peroxide and peroxynitrite needed to protect anti-microbial drugs, while protecting and increasing the levels of Nitric Oxide needed to enhance viral destruction in HSV-1 infected cells. The combination of alpha-keto acids along with an antiviral drug was synergistic in totally eliminating the viral infection in HSV-1 infected cells.