K. M. A. Welch

EFFECT OF TRANSIENT ISCHEMIA ON MONOAMINE LEVELS IN THE CEREBRAL CORTEX OF GERBILS1,2

Abstract— Cortical monoamine changes during ischemic episodes of varied duration and their sequence of changes following cerebral reperfusion were studied in the gerbil. Forty‐one percent of 280 animals exhibited signs of cerebral hemispheric ischemia (stroke) after unilateral common carotid artery occlusion. Norepinephrine (NE) levels decreased after 60 min in the occluded hemisphere of stroked animals but dopamine (DA) levels were unaltered. S‐Hydroxytryptamine (5‐HT) levels became bilaterally reduced in both stroked and non‐stroked animals as soon as S min after occlusion.

Ischemic anoxia and cerebral serotonin levels

Abstract Cerebral arteriovenous (A-V) differences for whole blood 5-HT were studied during and after ischemic anoxia to the brain stem and cerebral cortex produced by serial occlusion of both vertebral and carotid arteries in 12 baboons. Ischemia of the brain stem and possibly the cerebral cortex caused release of 5-HT into the cerebral venous blood. When cerebral blood flow was restored, 5-HT accumulated in the brain. These observations are discussed in relation to the symptomatology of cerebrovascular disease.

Neurotransmitter precursor amino acids in the treatment of multi-infarct dementia and Alzheimer's disease.

Ten patients with severe dementia due to Alzheimers disease (AD) or multi‐infarct dementia (MID) or both, were treated with the precursor amino acids of the neurotransmitters serotonin and dopamine. The precursor amino acids (PAA) were given orally in a preparation that included tyrosine (4 gm daily) and 5‐hydroxytryptophan (5‐HTP) (800 mg daily), plus carbidopa (100 mg daily) as an aromatic amino‐acid decarboxylase inhibitor. Diagnosis was established by an electroencephalogram, brain scan, computerized axial tomographic scan, and in one case by necropsy findings. Serial clinical evaluations and measurements of neuropsychologic function were performed. Levels of homovanillic acid (HVA) and 5‐hydroxyindoleacetic acid (5‐HIAA) were determined before and after administration of probenecid. Side effects of the PAA therapy were diarrhea, drowsiness, nausea, vomiting and agitation, all of which were controlled by reducing the dosage. One patient with MID and one with AD + MID showed clinical and psychologic improvement, but the others did not improve. Analysis of the cerebrospinal fluid for HVA and 5‐HIAA before and after the probenecid test indicated some improvement in the metabolic turnover of these acid metabolites of serotonin and dopamine after administration of their precursor amino acids.

Cerebrovascular response to intracarotid injection of serotonin before and after middle cerebral artery occlusion

The effect of intracarotid injection of serotonin (5-HT) on internal carotid artery flow and oxygen availability (O2a) of the cerebral cortex was studied in 10 baboons. Vasoconstriction occurred in the vascular bed of the territory supplied by the injected artery. After one middle cerebral artery was occluded the vasoconstrictor effect of 5-HT was more pronounced, particularly in the non-ischaemic hemisphere. The capacity of the cerebral vessels to provide collateral blood flow was reduced in both ischaemic and non-ischaemic areas of brain. As a result of focal cerebral ischaemia, 5-HT may accumulate in the brain and contribute to the progression of infarction.

Acute tissue response to cerebral ischemia in the gerbil. An ultrastructural study.

The Mongolian gerbil, because of the uniqueness of the anatomical features of its circle of Willis, has become an increasingly useful model in the study of cerebrovascular disease. The present work defines acute changes at the ultrastructural level following ischemic insult. The pathomorphological responses include initial astrocytic involvement and, when the degree of insult is increased, a progression of morphological changes is evident in neuronal and other parenchymal elements. Animals with vessels occluded for more than 3 hr without neurological signs suggestive of ischemia exhibited limited perivascular edema. Contralateral changes (perivascular astrocytic) were observed in the basal ganglia at 24 hr in animals with neurological deficit. Astrocytic and basal ganglia susceptibility to ischemia was consistent with previous findings in primate models. An additional association was found in that limited edematous involvement could exist in animals without neurological deficit but neuronal changes were only present in animals with signs of ischemic neurological deficit.

Biochemical comparison of migraine and stroke.

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ABNORMAL CT-SCANS IN MIGRAINE

SYNOPSIS

Psychological stress reduces cyclic 3',5'-adenosine monophosphate levels in the cerebral cortex of conscious rats, as determined by a new cryogenic method of rapid tissue fixation.

Abstract— Cryoplates were implanted on the surface of the cortex in 32 chronic rat preparations. These devices were used both to freeze and to extract small samples of tissue. Coolant was circulated through each device by small flexible polyethylene tubes. Two series of experiments were performed. In the first, the animals were unrestrained and showed no behavioral signs of stress during the freeze fixation. The temperature responses of the cryoplates were very rapid (−632°C/s), and samples more than 1 mm thick were frozen and extracted within a few hundred ms following the onset of cooling. Each sample was analyzed for 3′.5′‐adenosine monophosphate (cyclic AMP) and protein content. The results from the cryoplate group (25.6 ± 15.6pmol cyclic AMP/mg protein) were compared to those obtained from two other groups in which freeze fixation was produced by immersion in liquid nitrogen (13.6 ± 4.6pmol/mg protein) or decapitation into liquid nitrogen (18.6 + 7.6pmol/mg protein). In the second series of experiments, three types of stress (limb restraint, non‐adaptation to the experimental situation, and moderate cutaneous electric shock) were induced separately in order to determine the influence of each on cortical levels of cyclic AMP. Control animals were highly adapted to the experimental situation, freely moving and not shocked. The samples from each of the stressed groups showed a statistically significant (P≤. 0.01) reduction in cyclic AMP in comparison with the level in the controls (control: 29.3 pmol/mg protein; restrained: 14.2pmol/mg protein; unadapted: 9.6pmol/mg protein; shocked: 7.1 pmol/mg protein). Thus, psychological and physical stress reduced cyclic AMP content in parietal cortex.

Relationship of cerebral blood flow and metabolism to neurological symptoms.

Publisher Summary The past two decades have seen the gradual decline of the attitude of pessimism with which the physician approached the problem of treating patients with clinically proven cerebrovascular disease. The chapter discusses thr work done by early investigators to develop methods for measuring CBF and metabolism and the efforts of the numerous workers in our laboratory to refine and improve upon these methods. Experimental animals are first used, and if the techniques proved reliable and appropriate, they are applied to the study of patients with cerebrovascular disease. The second section discusses the results of such studies in experimental animals and human subjects. The techniques and certain of the special devices are also found to be applicable in the study of other neurological disorders such as epilepsy, and the results of these applications are discussed. However, this section deals with the physiology and pathophysiology of cerebrovascular function in health and disease in light of results from experiments in animals and studies in the patient with stroke. The third and final section is concerned with present concepts of medical and surgical treatment of patients with cerebrovascular disease or stroke.

Neurochemical Alterations in Cerebrospinal Fluid in Cerebral Ischemia and Stroke

This chapter is a review of cerebrospinal fluid (CSF) studies that support the hypothesis that the disrupting effect of cerebral ischemia on certain central neurotransmitter systems may be responsible for the pathophysiological changes and deficits in brain function that complicate cerebrovascular disease. Any investigator interested in the precise mechanisms of disease should find the study of ischemic effects on brain function a daunting one. Even when the pattern of ischemia can, to a degree, be controlled, as it is in experimental models, the effects of reduced blood flow are catastrophic for the physiological function of many brain systems. Interpretation of the results is therefore hazardous at the outset and even more so in man, in whom ischemia is more often than not variable in onset, site, degree, and despite the advent of computed tomographic (CT) scanning, frequently difficult to define. Nevertheless, if, by examining the CSF, which is the “sink” for many products of brain metabolism, it can be determined that there is deviation from normality, then this primarily phenomenological approach can initiate and justify more extensive mechanistic studies in experimental animals, and with the development of positron-emission tomography, eventually in man.