Quantification of gait in dystonic Gunn rats

Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups

“…(Sigma Chemical, St Louis, MO), a long-acting sulfonamide to induce BIND, or an equal volume of vehicle (control). Sulfa acutely displaces bilirubin from albumin (24,25), increases brain bilirubin content (26), and induces characteristic neurobehavioral abnormalities of acute bilirubin encephalopathy (24,25,27). Pups were killed with pentobarbital sodium (50 mg/kg i.p.…”

“…), and the cerebellum was rapidly removed, snap-frozen in liquid nitrogen, and stored at −80 °C while the pups were in a deeply anesthetized state. The cerebellum was the focus of study as this CNS region is the most adversely affected in the Gunn rat model (10,25,28), exhibits the highest brain bilirubin content (26), and is the site of neuropathology underlying much of the Gunn rat neurobehavioral phenotype (ataxia, gait abnormality, and movement disorder) during BIND (27).…”

“…Pups were monitored for signs of neuromotor dysfunction 24 h postsulfa dosing immediately before being killed and were assigned a BIND score using a previously described numeric rating scale that quantifies gait abnormalities and dystonia on a scale of 0-5 based on the following findings: 0 = normal; 1 = mildly abnormal with slight hindlimb ataxia, dystonia, and gait abnormality; 2 = mild hindlimb ataxia, dystonia, and gait abnormality with impaired righting reflex; 3 = abnormal as in 2, but with a more severe movement disorder and prolonged righting reflex; 4 = severe failure of locomotion, general lack of spontaneous movement with occasional bursts of hyperactivity and no righting reflex; and 5 = moribund including seizures and/or agonal respirations (27). The evaluator was not blinded to genotype as j/j animals are overtly jaundiced but was blinded to treatment assignment (sulfa, vehicle, MNC, PMIN, and TUDCA).…”

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

“…ABE does not occur spontaneously in Gunn rat pups of the current era, but must be induced by the administration of: (i) sulfadimethoxine to displace bilirubin from albumin [21,28,29], or (ii) phenylhydrazine to produce hemolysis [30]. These conditions result in markedly elevated CNS bilirubin levels [31,32] and overt signs of advanced bilirubin encephalopathy including severe neuromotor abnormalities [29,33] and abnormal ABER [28,30,34]. A small percentage of Gunn rat pups will die due to the hazardously high CNS bilirubin levels during induced ABE.…”

“…Dystonia is also a prominent feature in Gunn rat pups [33,62,63] and neonatal Ugt1 -/--deficient mice [22,64] both robust models of kernicterus. The former is used as an experimental model of dystonia [33,62,63].…”