Ganciclovir Inhibits Neuroinflammation in Mouse Model of MS
The antiviral may quell microglial activation and neuroinflammation even in the absence of infection
The drug ganciclovir may quell inflammation in the MS brain by a mechanism distinct from the antiviral activity for which it is known, and without compromising immunity in the periphery, according to a study published in the Journal of Experimental Medicine (Ding et al., 2014).
Previous studies from professors of neurology Oluf Andersen, M.D., and Jan Lycke, M.D., Ph.D., of the MS Research Team at the University of Gothenburg in Sweden tested the related drug acyclovir and found no effect other than an association with fewer exacerbations (Lycke et al., 1996; Bech et al., 2002).
Ganciclovir and similar pharmaceuticals are prodrugs that yield nucleoside analogs when viral thymidine kinase cleaves them. The analogs insert into replicating viral DNA, interfering with DNA polymerase and thereby halting infection by cytomegalovirus, Epstein-Barr virus, and herpes simplex virus.
In the brain of a person with MS, ganciclovir interacts with microglia, the central nervous system phagocytes that, when activated, proliferate early in pathogenesis and promote neuroinflammation. The microglial reaction attracts T cells into the brain.
In the present study, Tony Wyss-Coray, Ph.D., a professor of neurology at the Stanford University School of Medicine, and colleagues gave ganciclovir daily to wild-type mice both before and after induction of experimental autoimmune encephalomyelitis (EAE), using doses close to those that humans take for viral infections. They also tested the drug in mice with kainic acid-induced seizures.
The effects of ganciclovir were dramatic if given before EAE induction, squelching microglial division and inflammation and blocking the rush of T cells into the brain and spinal cord. The remaining microglia were small and nonactivated. Yet at the same time, the drug failed to interfere with the immune response in the periphery, demonstrated by evoking an antibody response to ovalbumin.
Further tests assessed ganciclovir’s fate in the brain. Analysis with liquid chromatography/tandem mass spectrometry showed persistent virus in the CNS at 21 days but not in plasma. Investigators found a radiolabeled ganciclovir analog in the brain in EAE mice but not in naïve mice. And ganciclovir decreased the number of proliferating microglia in cell culture, even in the absence of thymidine kinase. The drug is specific to microglia and the macrophages from which they descend, with no effect on astrocytes or T cells.
The researchers conclude that although they did not investigate ganciclovir in humans, the drug should be studied further because of its clear effects on microglial proliferation and neuroinflammation in the EAE mouse model.
Key open questions
- What are the effects of ganciclovir on MS pathogenesis in patients?
- What is the mechanism of ganciclovir’s effects on microglia in the absence of viral thymidine kinase?
- Have people with MS reported improvement during times when they are taking antivirals for infection?
Disclosures and sources of funding
The authors of the Journal of Experimental Medicine article claim no disclosures. Their funding came from the NIH and the Department of Veterans Affairs. Dr. Tyler has consulted for Biogen Idec, Genentech, Pfizer, Johnson & Johnson, and the PML Consortium.