Brain pathology caused in the neonatal macaque by short and prolonged exposures to anticonvulsant drugs

NEUROBIOLOGY OF DISEASE

卷:149

Article

Noguchi, Kevin K.¹  Fuhler, Nicole A.¹  Wang, Sophie H.¹  Capuano, Saverio, III²  Brunner, Kevin R.²  Larson, Shreya²  Crosno, Kristin²  Simmons, Heather A.²  Mejia, Andres F.²  Martin, Lauren D.³  Dissen, Gregory A.⁴  Brambrink, Ansgar⁵  Ikonomidou, Chrysanthy⁶ 

[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[2] Wisconsin Natl Primate Res Ctr, Madison, WI USA

[3] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Comparat Med, Beaverton, OR USA

[4] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR USA

[5] Columbia Univ, New York Presbyterian Hosp, Irving Med Ctr, Dept Anesthesiol, New York, NY USA

[6] Univ Wisconsin, Sch Med, Dept Neurol, Madison, WI USA

关键词: Antiepileptic;    Anticonvulsant;    Sedative;    Brain injury;    Apoptosis;    Development;    Barbiturate;    Benzodiazepine;   

DOI  :  10.1016/j.nbd.2020.105245

来源: Elsevier

【 摘 要 】

Barbiturates and benzodiazepines are potent GABAA receptor agonists and strong anticonvulsants. In the developing brain they can cause neuronal and oligodendroglia apoptosis, impair synaptogenesis, inhibit neurogenesis and trigger long-term neurocognitive sequelae. In humans, the vulnerable period is projected to extend from the third trimester of pregnancy to the third year of life. Infants with seizures and epilepsies may receive barbiturates, benzodiazepines and their combinations for days, months or years. How exposure duration affects neuropathological sequelae is unknown. Here we investigated toxicity of phenobarbital/midazolam (Pb/M) combination in the developing nonhuman primate brain. Neonatal rhesus monkeys received phenobarbital intravenously, followed by infusion of midazolam over 5 (n = 4) or 24 h (n = 4). Animals were euthanized at 8 or 36 h and brains examined immunohistochemically and stereologically. Treatment was well tolerated, physiological parameters remained at optimal levels. Compared to naive controls, Pb/M exposed brains displayed widespread apoptosis affecting neurons and oligodendrocytes. Pattern and severity of cell death differed depending on treatment-duration, with more extensive neurodegeneration following longer exposure. At 36 h, areas of the brain not affected at 8 h displayed neuronal apoptosis, while oligodendroglia death was most prominent at 8 h. A notable feature at 36 h was degeneration of neuronal tracts and trans-neuronal death of neurons, presumably following their disconnection from degenerated presynaptic partners. These findings demonstrate that brain toxicity of Pb/M in the neonatal primate brain becomes more severe with longer exposures and expands trans-synaptically. Impact of these sequelae on neurocognitive outcomes and the brain connectome will need to be explored.