Catálogo de publicaciones - libros

The term 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 in this volume grew out of initial experiments in the laboratory of Donald J. Reis in 1980–1981. The initial experimental challenge was how to selectively destroy baroreceptor afferents that make up a small portion of the vagus and glossopharyngeal nerves. The strategy chosen was to develop a technique using toxin retrogradely transported from an application site on the peripheral baroreceptor nerves in the neck. First attempts used low-molecular-weight cytotoxic drugs, such as doxorubicin, and were unsuccessful. Reasoning that the initial lack of success reflected inadequate delivery of toxin to the cell bodies, a plan was developed to attach these drugs to a well-transported agent, such as wheat germ agglutinin, which at the time was introduced as a highly effective anatomical tracer (). However, a simpler option seemed attractive. If a lectin such as wheat germ agglutinin was well transported, then perhaps a toxic lectin such as ricin or abrin would work. In retrospect, Harper and colleagues () had previously shown evidence for retrograde axonal transport of ricin, but this publication was discovered only after the initial suicide transport experiments applied ricin to the vagus nerve ().

The designation of (RIPs; reviews in refs. –) 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 , and abrin, from the seeds of .

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 with the degree of dementia (,). Subsequent research confirmed that cholinergic neurons originating in the nucleus basalis of Meynert, the diagonal band of Broca, and the medial septal nucleus, which terminate mainly in the cortex, olfactory bulb, and hippocampus (,), are destroyed in the progression of Alzheimer’s disease. This loss occurred earlier than the degeneration of other types of neurons, and the scale of this cholinergic cell death was massive. The similarity to dopaminergic depletion in Parkinson’s disease was evident, and the cholinergic hypothesis for the dementia of Alzheimer’s disease was proposed. The need for an animal model to test therapeutic strategies fueled basic research about the function of this cholinergic basal forebrain (CBF) system.

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 occupy much of the cytoplasm of particular pyramidal neurons.

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 (–). As discussed elsewhere (), attentional functions represent a crucial set of cognitive variables that contribute to the efficacy of learning and recalling of declarative information. Thus, impairments in attentional abilities rapidly yield escalating impairments in learning and memory. Different types of dysregulation of cortical cholinergic transmission have been hypothesized to mediate the diverse attentional impairments that are characteristic of major neuropsychiatric disorders and that contribute to the manifestation of the main cognitive symptoms of these disorders (–).

Two factors led to the emergence of the “cholinergic hypothesis of geriatric memory dysfunction” (): evidence that cholinergic blockade in human volunteers leads to impaired acquisition of new information (,) 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 (–). It has been proposed that it is the loss of the rising cholinergic pathways from the basal forebrain to the cortex (including the hippocampus) that is responsible for the amnesia seen in dementing illnesses (). This view has been challenged (e.g., in ref. ). Cholinergic antagonists also block transmission at cholinergic neurons intrinsic to many subcortical areas and block transmission in the cholinergic projections to noncortical areas; this may affect memory, either directly or via an influence on arousal and attention. Furthermore, studies with rats did not produce a correlation between the magnitude of cholinergic loss in the basal forebrain across various nonimmunotoxic lesion techniques and learning or performance impairments ().

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 (). Although glycogen, the major storage form of glucose, contributes dynamically to brain energy metabolism, it is present in very limited quantities (). 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 has focused on the neural organization of controls that maintain blood glucose concentrations. The immunotoxin, antidopamine β-hydroxylase (anti-DβH) conjugated to saporin (anti-DβH-sap) (–), has been an invaluable tool for establishing the importance of hindbrain catecholamine neurons for coordinated arousal of critical behavioral, autonomic, and neuroendocrine responses to glucose deficit. The goal of this review is to describe our use of anti-DβH-sap in demonstrating the essential roles of hindbrain catecholamine neurons in glucoregulation.

Central nervous system (CNS) adrenergic neurons are located exclusively in the medulla oblongata (). The metabolism of CNS adrenaline, its turnover rate, and its pharmacology were intensely studied in the late 1970s (reviewed in ref. ). Since then, the study of CNS adrenergic neurons has been the purview of integrative physiologists interested in stress, autonomic regulations, and the neural control of blood pressure and glucose. The CNS contains three clusters of adrenergic neurons: C1, C2, and C3 (). The main focus of this chapter is on the C1 neurons, especially those with spinal projections that are most important for sympathetic control and blood pressure regulation (–).

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 this topic ().