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The term molecular neurosurgery has been applied to several different experimental strategies, including a variety of genetic manipulations. For the purposes of this book, the term is used to refer to the use of targeted cytotoxins to produce highly selective neural lesions. Used in this sense, the term is relevant to both experimental and potential clinical applications. The body of work addressed...
The designation of ribosome-inactivating proteins (RIPs; reviews in refs. 1–4) has been applied to plant proteins that enzymatically damage ribosomes in a catalytic manner, thus inhibiting protein synthesis (Table 1). The first identified RIPs were two potent toxins, known for more than a century: ricin, from the seeds of Ricinus communis, and abrin, from the seeds of Abrus precatorius.
Selective lesioning of the cholinergic neurons in the basal forebrain nuclei was a highly sought goal for use as an animal model of Alzheimer’s disease. Autopsy studies of Alzheimer’s-diseased brain tissue found that a substantial loss of the cholinergic innervation of the cerebral cortex and hippocampus was a prominent feature of this disease, and the degree of this neuron loss was highly correlated...
Alzheimer’s disease, the most common neurodegenerative disorder causing senile dementia, is characterized by two major morphopathological hallmarks. The deposition of extracellular neuritic, β-amyloid peptide-containing plaques (senile plaques) in hippocampal and cerebral cortical regions of patients with Alzheimer’s disease is accompanied by the presence of intracellular neurofibrillary tangles that...
The anti-p75-immunotoxin 192 immunoglobulin G-saporin (192 IgG-sap) has been instrumental in testing the hypothesis that the integrity of the cortical cholinergic input system is necessary for the mediation of a wide range of attentional functions and capacities (1–10). As discussed elsewhere (11), attentional functions represent a crucial set of cognitive variables that contribute to the efficacy...
Two factors led to the emergence of the “cholinergic hypothesis of geriatric memory dysfunction” (1): evidence that cholinergic blockade in human volunteers leads to impaired acquisition of new information (2,3) and the demonstration of loss of cortical cholinergic activity and loss of cholinergic cell bodies in the basal forebrain of patients dying with Alzheimer’s disease (4–6). It has been proposed...
There are 4 million Americans with Alzheimer’s disease (AD), and the cost of the disease to the United States is estimated at $100 billion annually (Alzheimer’s Association). Finding a cure or prevention for AD is therefore an important goal. To do this, however, the cause(s) of AD must first be determined.
Glucose is the essential substrate for brain energy metabolism (1). Although glycogen, the major storage form of glucose, contributes dynamically to brain energy metabolism, it is present in very limited quantities (2). Thus, the brain requires continuous delivery of glucose by the blood. Clearly, then, the control of blood glucose is of fundamental importance for brain metabolism. Work in our laboratory...
Central nervous system (CNS) adrenergic neurons are located exclusively in the medulla oblongata (1). The metabolism of CNS adrenaline, its turnover rate, and its pharmacology were intensely studied in the late 1970s (reviewed in ref. 2). Since then, the study of CNS adrenergic neurons has been the purview of integrative physiologists interested in stress, autonomic regulations, and the neural control...
Several saporin-containing targeted toxins have been used in studies of nociception/pain. This chapter reviews this exciting area, including some of our most recent work. Certainly, substance P-saporin (SP-sap), the first conjugate used for pain research, has generated the most data and interest, but a number of other saporin conjugates have been introduced, and others are on the way. A review discusses...
Virtually all organisms manifest regular periods of behavioral quiescence and activity. In mammals and birds, these periods have evolved into regular episodes of wakefulness and sleep. The sleep period itself has further differentiated into two distinct states, slow wave sleep (SWS) and rapid eye movement (REM) sleep. In humans, SWS has further differentiated into four distinct stages, each identified...
Lectins are carbohydrate-binding proteins that recognize distinct oligosaccharide moieties of glycoproteins and glycolipids. In vertebrates, endogenous lectins serve a variety of functions, including cell adhesion, cell recognition, signal transduction, and endocytosis, in both neuronal and nonneuronal cells (1–5). A role for cell surface carbohydrate recognition has been described in processes, such...
Saporin conjugates have proven extremely versatile and valuable in the selective destruction of a variety of cell types. In the nervous system, the use of saporin-conjugated toxins has generally been directed toward neurons. We were interested in whether saporin conjugates could be used to target other nervous tissue cell types, particularly the myelin-forming cells. Taking advantage of the fact that...
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