Time-dependent changes in cerebral choline and acetylcholine induced by transient global ischemia in rats.

Abstract

We occluded the carotid and vertebral arteries of 12 rats for 15 minutes to measure the brain concentrations of choline and acetylcholine and cerebral blood flow at the end of the ischemic period or 15,30, or 150 minutes after circulation was reestablished. The animals were sacrificed with microwave radiation focused to the head immediately after a brief infusion of [ 14 C]iodoantipyrine with rapid sampling of arterial blood. Brain tissue samples were extracted with ether to separate the tracer, which was subsequently measured by liquid scintillation counting and used to calculate local cerebral blood flow. The aqueous phase was then processed for the measurement of choline and acetylcholine concentrations by gas chromatography/mass spectrometry. The results showed a large increase in tissue choline content and a decrease in tissue acetylcholine content during ischemia. During recirculation, choline levels progressively declined, reaching levels lower than those in four control rats after 150 minutes of recirculation for most brain regions. A reciprocal relation between the brain choline concentration and local cerebral blood flow was found. Acetylcholine levels showed an initial rebound to greater than control during recirculation, with subsequent normalization. Brain acetylcholine concentration was positively correlated with brain choline concentration, provided that cerebral blood flow was >03 mlxg'xmin" 1 . Because tissue free choline was depleted in most brain regions 150 minutes after transient ischemia, we speculate that prolonged ischemia may produce a greater depletion of tissue free choline with a resulting decline in tissue acetylcholine. This could play an important role in the cognitive deficit associated with vascular dementia. (Stroke 1991^22:643-647) A cetylcholine is a neurotransmitter of crucial importance in the central nervous system. Only a few studies have addressed alterations in the cerebral concentrations of this molecule under ischemic conditions. The concentrations of both precursors of acetylcholine, choline and acetylcoenzyme A (acetyl-CoA), are known to be affected by the level of cerebral blood flow (CBF). Within the brain, choline is continuously produced by hydrolysis of phospholipids and acetylcholine and reutilized for synthesis of phospholipids and acetylcholine. These processes normally result in a net production of free choline that is washed away by the circulation and is reflected in a higher cerebral venous than arterial concentration.1 -4 As a consequence, an inverse rela- Received October 16, 1990; accepted January 23, 1991. tion between CBF and tissue choline level occurs during focal cerebral ischemia. 3 This effect tends to enhance the rate of acetylcholine synthesis by a precursor-loading mechanism when CBF decreases. Acetyl-CoA used for acetylcholine synthesis, on the other hand, originates from pyruvate, the concentration of which is known to decrease during ischemia. 6 Thus, a reduction of CBF will potentially affect acetylcholine synthesis in opposite ways by...

Intrinsically Low Open Probability of α7 Nicotinic Acetylcholine Receptors Can Be Overcome by Positive Allosteric Modulation and Serum Factors Leading to the Generation of Excitotoxic Currents at Physiological Temperatures

“…This could be especially true in cases of trauma or stroke, when choline concentrations in the brain increase to as high as 100 M (Jope and Gu, 1991;Scremin and Jenden, 1991).…”

Preventive Effect of Chotosan, a Kampo Medicine, on Transient Ischemia-Induced Learning Deficit Is Mediated by Stimulation of Muscarinic M1 But Not Nicotinic Receptor

“…20,21) Moreover, many studies have demonstrated that ischemia causes a reduction of memory and judgment that is associated with the cholinergic dysfunction in affected brain areas 22) and that ischemic insults decreases in ACh level in the affected regions of the brain. [23][24][25] Thus, in animals subjected to transient ischemia, an impairment of spatial cognitive performance in a water maze task is likely attributed to dysfunction of the central cholinergic system due to disturbance of energy metabolism and hypoxia in the ischemic brain. Consistent with previous reports from this 3,11) and other laboratories, 26,27) we found that transient ischemia caused a significant reduction of the ACh level in the hippocampus and that pretreatment with a cholinesterase inhibitor tacrine produced a protective effect not only on learning deficits but also on the reduction of the hippocampal ACh level in T2VO mice.…”

Regulation of Neuronal Function by Choline and 4OH-GTS-21 Through α7 Nicotinic Receptors

“…Choline is accumulated in all tissues via simple diffusion or specific carrier mechanisms (Zeisel et al 1980). Under normal physiological conditions, the brain concentration of choline varies within a range of 10 -20 M and can rise to over 100 M in a number of pathophysiological conditions attributed to abnormal phospholipid metabolism, such as neural trauma and chronic degenerative disorders, including Alzheimer's disease (Farooqui and Horrocks 1994;Jope and Gu 1991;Klein et al 1997;Scremin and Jenden 1991).…”