A dose-response study of ibogaine-induced neuropathology
in the rat cerebellum.
Xu Z,1 Chang LW,1,2 Slikker W Jr,2,3 Ali SF,2,3
Rountree RL,3 Scallet AC.2,3
Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga.
It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin.
IBO has both psychoactive and stimulant properties. In single-blind trials with humans, it
ameliorated withdrawal symptoms and interrupted the addiction process. However, IBO also produced
neurodegeneration of Purkinje cells and gliosis of Bergmann astrocytes in the cerebella of
rats given even a single dose (100 mg/kg, ip). Here, we treated rats (n = 6 per group) with
either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of
IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and
axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and
Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same
pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons.
All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but
the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected;
despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of
astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm
the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of
the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls,
indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).
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