crotononitrile and Nerve-Degeneration

Konzo and lathyrism are associated with consumption of cassava and grass pea, respectively. Cassava consumption has also been associated with a third disease, tropical ataxic neuropathy (TAN). This review presents a new unifying hypothesis on the causative agents for these diseases: namely, that they are nitriles, compounds containing cyano groups. The diseases may be caused by different but similar nitriles through direct neurotoxic actions not mediated by systemic cyanide release. Both cassava and Lathyrus contain nitriles, and other unidentified nitriles can be generated during food processing or in the human body. Available data indicate that several small nitriles cause a variety of neurotoxic effects. In experimental animals, 3,3'-iminodipropionitrile (IDPN), allylnitrile and cis-crotononitrile cause sensory toxicity, whereas hexadienenitrile and trans-crotononitrile induce selective neuronal degeneration in discrete brain regions. IDPN also induces a neurofilamentous axonopathy, and dimethylaminopropionitrile is known to cause autonomic (genito-urinary) neurotoxicity in both humans and rodents. Some of these actions depend on metabolic bioactivation of the parental nitriles, and sex- and species-dependent differences in susceptibility have been recorded. Recently, neuronal degeneration has been found in rats exposed to acetone cyanohydrin. Taken together, the neurotoxic properties of nitriles make them excellent candidates as causative agents for konzo, lathyrism and TAN.

Topics: Aminopropionitrile; Animals; Brain; Cyanides; Humans; Lathyrism; Lathyrus; Manihot; Molecular Structure; Nerve Degeneration; Neurotoxins; Nitriles

The inferior olive climbing fibre projection is key to cerebellar contributions to motor control. Here we present evidence for a novel tool, trans-crotononitrile (TCN), to selectively inactivate the olive to study its functions. Anatomical, electrophysiological and behavioural techniques have been used in rats to assess the CNS effects of TCN, with a focus on the olivocerebellar projection. These findings were compared with those obtained with 3-acetylpyridine (plus nicotinamide administered 3.5 h later, 3AP + 3.5 h). Fluoro-Jade B cell labelling showed that TCN and 3AP + 3.5 h induce neurodegeneration primarily within the inferior olive, with no other targets in common. Recordings of evoked field potentials on the cerebellar cortical surface showed that both neurotoxins can reduce transmission in climbing fibre but not mossy fibre pathways. Both histological and electrophysiological differences suggest that TCN and 3AP have distinct mechanisms of action. Estimates of the numbers of surviving cells within individual subdivisions of the olive indicate that TCN and 3AP + 3.5 h cause different patterns of subtotal olivary lesion: most surviving neurons are present in the rostral (TCN) or caudal (3AP + 3.5 h) parts of the medial accessory olive, which are associated with two different cerebellar modules: the C2 and A modules, respectively. In behavioural studies, TCN and 3AP + 3.5 h produced differences in motor deficits consistent with the notion that these cerebellar modules have distinct functional responsibilities. Thus, studies using TCN as compared with 3AP + 3.5 h have the potential to shed light on the contributions of different cerebellar modules in motor control.

Topics: Animals; Brain; Brain Mapping; Cell Count; Dose-Response Relationship, Drug; Evoked Potentials; Exploratory Behavior; Gait; Male; Multivariate Analysis; Nerve Degeneration; Nerve Fibers; Neurons; Neurotoxins; Nitriles; Olivary Nucleus; Psychomotor Performance; Pyridines; Rats; Rats, Long-Evans; Time Factors