Neuroexcitatory actions of Tamiflu and its carboxylate metabolite

Abstract

Oseltamivir (Tamiflu) is now being stockpiled by several governments as a first line treatment for an anticipated outbreak of avian influenza caused by H5N1. However, abnormal behaviors and death associated with the use of Tamiflu have developed into a major issue in Japan where Tamiflu is often prescribed for seasonal influenza. Thus, it is critical to determine neuropsychiatric effects of oseltamivir and to establish methods for safe administration. Using juvenile rats and rat hippocampal slices, we investigated whether oseltamivir has adverse effects on the central nervous system. Systemic injection of oseltamivir (50mg/kg i.p.) produced no change in behavior within 2h. However, prior injection of oseltamivir significantly altered the duration of loss of lightning reflex following ethanol injection (3.3g/kg, i.p.). Ethanol injection in the presence of oseltamivir also resulted in enhanced hypothermia. In the CA1 region of hippocampal slices, oseltamivir (100 microM) induced paired-pulse facilitation in population spikes without changes in excitatory postsynaptic potentials. Similarly, 3 microM oseltamivir carboxylate, the active metabolite of oseltamivir, facilitated neuronal firing, though the facilitation did not involve GABAergic disinhibition. Moreover, oseltamivir carboxylate produced further facilitation following administration of 60mM ethanol. These findings indicate that oseltamivir has effects on the central nervous system, especially when combined with other agents.

Figure 1

A, B. Oseltamivir (100 μM, A) and 3 μM OCB (B) facilitated 2^nd PS and 2^nd somatic EPSPs (sEPSPs) with little change in other parameters. C. In slices preincubated with 3 μM OCB for 2 hours, 60 mM ethanol (open bar) did not change PSs, sEPSPs or dendritic EPSPs (dEPSPs). However, following washout of ethanol, 2^nd PS and 2^nd sEPSPs were augmented. Traces depict PSs (top) and dEPSPs (bottom in each panel) recorded 10 min before (dotted lines) and 30 min after (solid lines) drug administration (A, B) or 30 min after washout of ethanol (C). Scale: 1 mV, 5 msec.

Figure 2

A. PTX (1 μM) was administered starting 40 min before time 0. PSs, somatic EPSPs (sEPSPs) and dendritic EPSPs (dEPSPs) evoked by the first (open circles) and second pulses (filled circles) are stable during PTX. B. In PTX, 3 μM OCB facilitated 2^nd PSs and sEPSPs without altering other parameters. C. 4-AP (15 μM) was administered starting 40 min before time 0. Unlike PTX, all parameters were stable with 3 μM OCB in the presence of 4-AP. Traces depict PSs (top) and dEPSPs (bottom) at time 0 (dotted lines) and 60 min (solid lines). Scale: 1 mV, 5 msec.