Tracy Ann Perry

A new Alzheimer's disease interventive strategy: GLP-1.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimers disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.

New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: p53 and TNF‐α Inhibitors, and GLP‐1 Receptor Agonists

Abstract: Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age‐related neurodegenerative disorders, such as Alzheimers disease, Parkinsons disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate‐limiting steps within the pathological cascade. Such targets include TNF‐α, p53, and GLP‐1 receptor. The cytokine TNF‐α is elevated in Alzheimers disease, Parkinsons disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimers disease toxic peptide, Aβ, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and ‐oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon‐like peptide‐1 receptor (GLP‐1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults.

Glucagon‐like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons

Glucagon‐like peptide 1 (GLP‐1) activates receptors coupled to cAMP production and calcium influx in pancreatic cells, resulting in enhanced glucose sensitivity and insulin secretion. Despite evidence that the GLP‐1 receptor is present and active in neurons, little is known of the roles of GLP‐1 in neuronal physiology. As GLP‐1 modulates calcium homeostasis in pancreatic beta cells, and because calcium plays important roles in neuronal plasticity and neurodegenerative processes, we examined the effects of GLP‐1 on calcium regulation in cultured rat hippocampal neurons. When neurons were pre‐treated with GLP‐1, calcium responses to glutamate and membrane depolarization were attenuated. Whole‐cell patch clamp analyses showed that glutamate‐induced currents and currents through voltage‐dependent calcium channels were significantly decreased in neurons pre‐treated with GLP‐1. Pre‐treatment of neurons with GLP‐1 significantly decreased their vulnerability to death induced by glutamate. Acute application of GLP‐1 resulted in a transient elevation of intracellular calcium levels, consistent with the established effects of GLP‐1 on cAMP production and activation of cAMP response element‐binding protein. Collectively, our findings suggest that, by modulating calcium responses to glutamate and membrane depolarization, GLP‐1 may play important roles in regulating neuronal plasticity and cell survival.

Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.

Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.