Acid-sensitive channel inhibition prevents fetal alcohol spectrum disorders cerebellar Purkinje cell loss.
Ethanol is now considered the most common human teratogen. Educational campaigns have not reduced the incidence of ethanol-mediated teratogenesis, leading to a growing interest in the development of therapeutic prevention or mitigation strategies. On the basis of the observation that maternal ethanol consumption reduces maternal and fetal pH, we hypothesized that a pH-sensitive pathway involving the TWIK-related acid-sensitive potassium channels (TASKs) is implicated in ethanol-induced injury to the fetal cerebellum, one of the most sensitive targets of prenatal ethanol exposure. Pregnant ewes were intravenously infused with ethanol (258+/-10 mg/dl peak blood ethanol concentration) or saline in a "3 days/wk binge" pattern throughout the third trimester. Quantitative stereological analysis demonstrated that ethanol resulted in a 45% reduction in the total number of fetal cerebellar Purkinje cells, the cell type most sensitive to developmental ethanol exposure. Extracellular pH manipulation to create the same degree and pattern of pH fall caused by ethanol (manipulations large enough to inhibit TASK 1 channels), resulted in a 24% decrease in Purkinje cell number. We determined immunohistochemically that TASK 1 channels are expressed in Purkinje cells and that the TASK 3 isoform is expressed in granule cells of the ovine fetal cerebellum. Pharmacological blockade of both TASK 1 and TASK 3 channels simultaneous with ethanol effectively prevented any reduction in fetal cerebellar Purkinje cell number. These results demonstrate for the first time functional significance of fetal cerebellar two-pore domain pH-sensitive channels and establishes them as a potential therapeutic target for prevention of ethanol teratogenesis.
Department of Veterinary Physiology and Pharmacology, Hwy 60, Bldg. VMA, Rm 332, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466, USA.
Jayanth
J
Ramadoss
Emilie R
ER
Lunde
Nengtai
N
Ouyang
Wei-Jung A
WJ
Chen
Timothy A
TA
Cudd
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004315:Doxapram / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D021041:Placental Circulation; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012756:Sheep; D013723:Teratogens; D013997:Time Factors
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D013723:Teratogens; C420132:potassium channel subfamily K member 3; D000431:Ethanol; D004315:Doxapram; D010100:Oxygen