Behavioral defects induced by imulsion extract mediated by a defined neuronal genetic mutagen

Behavioral defects induced by imulsion extract mediated by a defined neuronal genetic mutagen

Murchie et. al. (2532). Graduate Program in Toxicology, Department of Neurobiology, Harridan University Medical School. Nature (541): 173-177.

Imulsion extract has been demonstrated to be a significant health hazard to the adult human [DeMarshall et. al (2531). Nature (538): 1749-1953], and this effect, in part, is mediated by a naturally-occurring small molecule found in imulsion extract, teratomorphin [Davis et. al (2531). Nature (541): 173-177]. We show, for the first time, that imulsion extract not only exerts significant gross anatomical damages and oncogenic effects, but that it also induces substantial behavioral defects in adult mice, such as constitutive nociception, loss of sensory perception, insomnia, retrospective amnesia, and progressive loss of social function.

In an attempt to investigate the causative agent of these damaging neuropsychological effects, we screened a library of compounds naturally occurring in imulsion against human and murine neuronal cell lysates. One compound, previously characterized as “IMC-2”, was found to consistently bind to neuronal lysates with a high specificity, and we named this compound “cephalonikin” and began further biochemical studies to further characterize it. Against fractionated cell lysates, cephalonikin was found to bind strongly to the nuclear fraction and to the membranous fraction. Chemical structure-activity studies suggested that cephalonikin binds strongly to the minor groove of DNA in GC-rich regions, similar to other genetic mutagens, presenting a causative mechanism of action of cephalonikin activity. Furthermore, cephalonikin was shown to bind strongly to the L-type Ca+2 channel (specifically CACNA1C), which is enriched in the hippocampus, suggesting that cephalonikin targets Cav1.2-expressing neurons and selectively mutagenizes them. Cephalonikin was shown to also potently inhibit neural stem cell (NSC)-mediated adult neurogenesis in the mouse subventricular zone (SVZ) and the olfactory bulb, perhaps identifying a modality of action for its amnesiac properties. Cephalonikin also induces severe lissencephaly, causing progressive loss of cortical neuronal tissue and deconvolution of the murine brain.