neuropeptide-y and Nervous-System-Diseases

It has been well established that there is bidirectional communication between the immune and central nervous systems. One context in which this interaction has been extensively studied is that of the stress response. Stress, whether physical or psychological, induces alterations in immune function. Often exposure to a stressor results in pro-inflammatory responses in the brain and periphery. These responses are mediated by a variety of inflammatory molecules including neuropeptides, cytokines, and stress hormones among others. Here, we will discuss several of the more comprehensively studied of these inflammatory mediators and their role(s) in stress-induced neurogenic inflammation.

Topics: Animals; Catecholamines; Cyclooxygenase 2; Cytokines; Glucocorticoids; Humans; Inflammation; Nervous System Diseases; Neuropeptide Y; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Stress, Psychological; Substance P

Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.

Topics: Analgesics, Opioid; Anticonvulsants; Blood-Brain Barrier; Dynorphins; Epilepsy; Galanin; Molecular Structure; Nervous System Diseases; Neuropeptide Y; Neuropeptides; Neurotensin; Seizures; Sequence Homology, Amino Acid; Somatostatin

Estrogen has diverse and powerful effects in the brain, including actions on neurons, glia, and the vasculature. It is not surprising, therefore, that there are many changes in the female brain as serum estradiol levels rise and fall during the normal ovarian cycle. At times of life when estradiol levels change dramatically, such as puberty, postpartum, or menopause, there also are dramatic changes in the central nervous system. Changes that occur because of fluctuations in serum estrogen levels are potentially relevant to neurological disorders because symptoms often vary with the time of the ovarian cycle. Moreover, neurological disorders (eg, seizures and migraine) often increase in frequency in women when estradiol levels change. In this review, the contribution of 2 growth factors targeted by estrogen, the neurotrophin brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), will be discussed. Estrogen-sensitive response elements are present on the genes for both BDNF and VEGF, and they are potent modulators of neuronal, glial, and vascular function, making them logical candidates to mediate the multitude of effects of estrogen. In addition, BDNF induces neuropeptide Y, which has diverse actions that are relevant to estrogen action and to the same neurological disorders.

Topics: Animals; Brain-Derived Neurotrophic Factor; Estradiol; Estrogens; Female; Humans; Migraine Disorders; Nervous System Diseases; Neuropeptide Y; Vascular Endothelial Growth Factor A

In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, and predicted that the effects of estrogen, at least in part, might be due to the induction of BDNF. This hypothesis is discussed with respect to the hippocampus, where substantial evidence has accumulated in favor of it, but alternate hypotheses are also raised. It is suggested that some of the interactions between estrogen and BDNF, as well as the controversies and implications associated with their respective actions, may be best appreciated in light of the ability of BDNF to induce neuropeptide Y (NPY) synthesis in hippocampal neurons. Taken together, this tri-molecular cascade, estrogen-BDNF-NPY, may be important in understanding the hormonal regulation of hippocampal function. It may also be relevant to other regions of the CNS where estrogen is known to exert profound effects, such as amygdala and hypothalamus; and may provide greater insight into neurological disorders and psychiatric illness, including Alzheimer's disease, depression and epilepsy.

Topics: Adult; Animals; Brain-Derived Neurotrophic Factor; Central Nervous System; Estrogens; Hippocampus; Humans; Intercellular Signaling Peptides and Proteins; Mental Disorders; Nervous System Diseases; Neuropeptide Y; Steroids

1. NPY is a 36 amino acid tyrosine-rich peptide. It is one of the most abundant and widely distributed neuropeptides known today within the central nervous system with particularly high concentrations in the hypothalamus and in several limbic regions. 2. NPY seems to coexist with other on neurotransmitters like somatostatin, galanin, GABA and the catecholamines noradrenaline and adrenaline in discrete brain regions. 3. NPY binding sites are widely distributed in the brain. However they do not always overlap with the distribution of NPY-like immunoreactivity. 4. NPY is suggested to be involved in a large number of neuroendocrine functions, stress responses, circadian rhythms, central autonomic functions, eating and drinking behaviour, and sexual and motor behaviour. 5. Psychotropic drugs and neurotoxins can alter the NPY concentrations in discrete brain regions. 6. It is possible that NPY is related to various neurological and psychiatric illnesses, like Huntington's chorea, Alzheimer's disease, Parkinson's disease, eating disorders, and major depressive illness.

Topics: Animals; Central Nervous System; Humans; Mental Disorders; Nervous System Diseases; Neuropeptide Y

Topics: Adenylyl Cyclase Inhibitors; Alzheimer Disease; Amygdala; Animals; Basal Ganglia; Behavior, Animal; Brain Stem; Cell Membrane Permeability; Central Nervous System; Cerebral Cortex; Chemical Phenomena; Chemistry; Hippocampus; Humans; Huntington Disease; Hypothalamus; Insulin; Insulin Secretion; Molecular Weight; NADPH Dehydrogenase; Nerve Tissue Proteins; Nervous System Diseases; Neuropeptide Y; Receptors, Cell Surface; Receptors, Somatostatin; Septal Nuclei; Somatostatin; Spinal Cord; Substantia Innominata

Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin- and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS.

Topics: Animals; Gene Expression Regulation; Mice; Nervous System Diseases; Neurons; Neuropeptide Y; Protective Agents; Retroviridae; RNA, Messenger

Topics: Animals; Central Nervous System; Humans; Nervous System Diseases; Neuropeptide Y; Peripheral Nervous System

Autonomic dysfunction is an increasingly recognized problem in aging animals and man. The pathologic changes that produce autonomic dysfunction in human aging are largely unknown; however, in experimental animal models specific pathologic changes have been found in selected sympathetic ganglia. To address whether similar neuropathologic changes occur in aging humans, the authors have examined paravertebral and prevertebral sympathetic ganglia from a series of 56 adult autopsied nondiabetic patients. They found significant, specific, age-related neuropathologic lesions in the prevertebral sympathetic superior mesenteric ganglia of autopsied patients. Markedly swollen dystrophic preterminal axons compressed or displaced the perikarya of principal sympathetic neurons. Ultrastructurally, these swollen presynaptic axons contained abundant disoriented neurofilaments surrounded by peripherally marginated dense core vesicles. Immunohistochemical studies demonstrated that dystrophic axons contained tyrosine hydroxylase and neuropeptide tyrosine (NPY)-like immunoreactivity but not other neuropeptides (VIP, substance P, gastrin-releasing peptide [GRP]/bombesin, met-enkephalin). Similar to the animal models of aging, lesions were much more frequent in the prevertebral superior mesenteric ganglia than in the paravertebral superior cervical ganglia. These studies demonstrate anatomic, peptidergic, and pathologic specificity in the aging human nervous system similar in many respects to that which the authors have described in experimental animal models. Neuroaxonal dystrophy in the sympathetic nervous system may underlie poorly understood alterations in clinical autonomic nervous system function that develop with age.

Topics: Adult; Aged; Aging; Autopsy; Axons; Enkephalin, Methionine; Ganglia, Sympathetic; Gastrin-Releasing Peptide; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Nervous System Diseases; Neurons; Neuropeptide Y; Peptides; Substance P; Synapses; Time Factors; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide