Hexachlorophene and Cuprizone Induce the Spongy Change of the Developing Rat Brain by Different Mechanisms: The Role of 2’, 3’-Cyclic Nucleotide 3’-Phosphodiesterase (CNPase)

Abstract

ABSTRACT. The goal of this research was to identify mechanisms responsible for the spongy change induced in rats after repeated hexachlorophene (HCP) or cuprizone (CPZ) dosing. Rats were dosed with 35 mg/kg HCP for 5 days followed by drug withdrawal for 7 days suffered spongy changes to the white matter of the cerebrum, cerebellum, medulla oblongata, and spinal cord that were accompanied by degeneration of oligodendroglia. The severity of both lesions increased prominently on day 5; however, the spongy change decreased and degeneration of oligodendroglia reversed on day 12 (7 days after dosing ceased). On day 12, cerebral cortex oligodendroglia were stained strongly by anti-CNPase. Other rats were fed for 8 days with powdered chow containing 1% (w/w) CPZ, which was then withdrawn for 16 days. The rats exhibited the spongy change in the white matter of the cerebrum and cerebellum as well as oligodendroglial cell death from day 3. The severity of both lesions increased prominently on day 8. Cerebral cortex oligodendroglia were stained strongly by anti-CNPase on days 3 to 8 and decreased to the control levels by day 24 (16 days after dosing ceased). Electron microscopy revealed that oligodendroglia frequently displayed apoptotic morphology. These findings suggest that CNPase expression was induced in the course of restoration following HCP-induced insults to oligodendroglia and the myelin sheath, and in the course of demyelination by CPZ-induced damage to oligodendroglia. However, the role of CNPase on both courses is unclear. KEY WORDS: CNPase, cuprizone, hexachlorophene, neurotoxicity, rat.doi: 10.1292/jvms.11-0469; J. Vet. Med. Sci. 74 (7): [837][838][839][840][841][842][843] 2012 Hexachlorophene (HCP), used as an antimicrobial agent in soaps, liquid detergents, and cosmetics during the 1960's [12,22], has also been widely used in agriculture as a plant fungicide and pesticide [12,13,22]. In 1969, however, Gump et al. [8] conducted experiments demonstrating that HCP was toxic chemical in a variety of animals, including mice, rats, guinea pig, dogs, and sheep. Moreover, Kimbrough and Gaines [13] described the HCP-induced spongy change in the cerebral white matter in rats. Considerable research has been subsequently devoted to studying the HCP-induced spongy change [4,12,13,16,22,23], which corresponds to the splitting of the intraperiod line of the myelin sheath [16].Cuprizone (CPZ), a potent copper chelator, causes the spongy change in the central nervous system of mice, guinea pigs, and rats [3,6,19]. CPZ treatment provides a model for toxic demyelination model characterized by this pathology [1,7,18]. The CPZ-induced spongy change is also accompanied by the same ultrastructural changes as those described above for HCP [3] and is believed to be caused by cytotoxic insults to oligodendroglia [3,19].Myelin basic protein (MBP) [2,5,10,15], proteolipid protein (PLP) [2,5,10], and CNPase [2,5,10,15,24] are specific markers expressed either in oligodendroglia or in the myelin. MBP and PLP are respectively associat...

Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity

“…This is caused by intracellular fluid influx and vacuolation, and in this respect is similar to the clinically important ischaemic brain oedema (Andreas 1993). It was suggested earlier that the spongy changes induced by hexachlorophene result from intramyelin accumulation of the fluid (Lampert et al, 1973;Towfighi, 1980) and cytotoxic insults to oligodendroglia (Kanno et al, 2012) in vivo.…”

Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

“…Intoxication by actinomycin D [36] copper [16] cuprizone [33], [42] ethidium bromide [50] hexachlorophene [18] isonicotinic acid hydrazide [21] lysolecithin [5] triethyltin [2] Genetic models of mitochondrial dysfunction reviewed in [43] altered proteolipid expression [3] Models of scrapie [24], [33] Veterinary pathologies of various aetiology…”

Perinatal methylmercury exposure perturbs the expression of Plp1 and Cnp splice variants in cerebellum of rat pups

“…The mRNA or protein levels of oligodendrocyte-enriched genes, such as Mbp (Padhi and Pelletier, 2012), Plp1 and Cnp can be useful biomarkers to assess perturbation of myelination. Perturbation of Plp1 gene expression was observed following exposure to cocaine (Kristiansen et al, 2009), nicotine (Cao et al, 2013), propylthiouracil (Kobayashi et al, 2009), while alteration of Cnp expression was observed after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Fernandez et al, 2010), aniline, cuprizone and hexachlorophene (Kanno et al, 2010(Kanno et al, , 2012. By the use of alternative promoters and alternative splicing, a gene can produce multiple transcript variants , which may have different and even antagonistic functional roles (Menon et al, 2011).…”