Human rabies therapy: lessons learned from experimental studies in mouse models

Ketamine was one of the therapeutic agents used as a therapy for a human rabies survivor who did not receive rabies vaccine. Ketamine therapy is re-examined here in infected mouse primary neuron cultures and in adult ICR mice using the CVS strain with both intracerebral and peripheral routes of inoculation with ketamine vs. vehicle given intraperitoneally. No significant beneficial therapeutic effects of ketamine in the cultures or mouse model were observed. This team does not recommend further widespread clinical use of ketamine on human rabies patients until further experimental work demonstrates therapeutic efficacy. Because of the potential neuroprotective and anti-apoptotic properties of minocycline, minocycline therapy was assessed in infected primary neuron cultures and in neonatal ICR mice infected by peripheral inoculation with a highly attenuated rabies virus strain. No beneficial effect of minocycline was observed in the primary neuron cultures. In the mouse model, minocycline therapy aggravated the clinical neurological disease and resulted in higher mortality. An anti-apoptotic effect of minocycline was noted in the brains of infected mice, which may have very mildly increased viral spread. An anti-inflammatory effect was also noted in the brain using a CD3 T cell marker. These effects likely aggravated the disease. This team recommends that empirical therapy with minocycline be avoided in the management of rabies and viral encephalitis in humans until more information becomes available.