dynorphins and Nervous-System-Diseases

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

This review addresses the main neuropathologic advances that have been made over recent years in the study of focal lesions in patients with epilepsy undergoing surgical treatment. There have been revisions and simplifications to the classification of focal cortical dysplasias. Hippocampal sclerosis is a well-characterized lesion but further pathologic studies have explored its possible relationship to temporal lobe developmental lesions, ongoing neurogenesis and mechanisms of its epileptogenicity. The important contribution of astrocytes to epileptogenesis is also unfolding and is briefly discussed, as are the possible cellular mechanisms of drug resistance.

Topics: Brain Neoplasms; Cytokines; Dynorphins; Epilepsy; Hippocampus; Humans; Immunohistochemistry; Nervous System Diseases; Neural Cell Adhesion Molecules; Sclerosis

A range of biologically different opioid peptides are synthesised as components of three distinct precursors, pro-opiomelanocortin, proenkephalin, and prodynorphin. They interact with a number of receptors which have so far been characterised as mu, delta, kappa, sigma, and epsilon. It is unclear which ligands bind to which receptors under physiological circumstances, but preferential in vitro interactions include enkephalins with delta receptors, dynorphin with kappa receptors, and beta-endorphin with epsilon receptors. Post-translational processing determines which of several opioid products are produced from each precursor, but the identity of the enzymes involved and regulation of processing is unknown. Opioid involvement in the neuroendocrine and cardiovascular systems is reviewed. Naloxone-sensitive opioid mechanisms are implicated in the control of gonadotrophin and adrenocorticotropic hormone secretion and in the hypotension of various types of shock. The investigation of possible dynorphin involvement in neurohypophysial function is taking place because vasopressin and dynorphin A (1-8) have been shown to coexist in the neurosecretory vesicles of magnocellular neurons.

Topics: Cardiovascular Diseases; Dynorphins; Endocrine System Diseases; Endorphins; Enkephalins; Female; Humans; Male; Nervous System Diseases; Protein Processing, Post-Translational; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa