Ratnakumari L, Qureshi I A, Maysinger D, Butterworth R F
Division of Medical Genetics, Sainte-Justine Hospital, Montreal, Quebec, Canada.
J Pharmacol Exp Ther. 1995 Jul;274(1):437-43.
The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal period similar to that seen in human patients. We studied the effect of congenital hyperammonemia on the development of cerebral cholinergic parameters such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and high-affinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf mutant mice were significantly elevated after weaning compared with control animals. ChAT activity levels started decreasing in mutant spf mice from the age of 30 days (i.e., immediately after weaning); it reached significantly lower levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice compared with controls up to the adult stage. However, there were no marked changes in the activity of AChE between control and hyperammonemic spf mice. The levels of beta-NGF, which is essential for cholinergic differentiation and function, were significantly lower in different brain regions of adult mutant mice compared with normal controls. A treatment of spf/spf breeding females with acetyl-L-carnitine, at a dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted in a significant restoration of ChAT activity levels in some brain regions of the spf/Y offspring. The beta-NGF levels were also significantly elevated after supplementation with ALCAR in mutant mice compared with untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR during cholinergic deficiency caused by congenital hyperammonemia.
稀毛（spf）突变小鼠存在X连锁的肝脏鸟氨酸转氨甲酰酶（OTC）缺陷，在出生后会出现高氨血症，这与人类患者的情况相似。我们研究了先天性高氨血症对spf小鼠脑胆碱能参数（如胆碱乙酰转移酶（ChAT）、乙酰胆碱酯酶（AChE）和高亲和力胆碱摄取（HACU））发育的影响。与对照动物相比，spf突变小鼠断奶后的血清氨水平显著升高。从30日龄（即刚断奶后）开始，突变的spf小鼠的ChAT活性水平开始下降；在成年动物中，其ChAT活性水平显著降低。直到成年阶段，spf/Y小鼠的HACU一直低于对照组（P <.01）。然而，对照小鼠和高氨血症spf小鼠之间的AChE活性没有明显变化。与正常对照相比，成年突变小鼠不同脑区中对胆碱能分化和功能至关重要的β-NGF水平显著降低。从受孕第1天开始，用1.5 mM的乙酰-L-肉碱处理spf/spf繁殖雌性小鼠，其spf/Y后代的某些脑区ChAT活性水平得到了显著恢复。与未处理的突变小鼠相比，补充ALCAR后突变小鼠的β-NGF水平也显著升高。这些数据表明，在先天性高氨血症引起的胆碱能缺乏期间，ALCAR具有神经营养特性。
