vasoactive-intestinal-peptide and Amyotrophic-Lateral-Sclerosis

Topics: Acetylcholinesterase; Amyotrophic Lateral Sclerosis; Anal Canal; Animals; Autonomic Nervous System Diseases; Catecholamines; Cholecystokinin; Enkephalins; Histocytochemistry; Humans; Male; Motor Neurons; Muscles; Neural Pathways; Pancreatic Polypeptide; Parasympathetic Nervous System; Pelvis; Penis; Rats; Somatostatin; Spinal Cord; Substance P; Urethra; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis treatment.

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Blotting, Western; Disease Models, Animal; Humans; Immunohistochemistry; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Vasoactive Intestinal Peptide

Degeneration of corpus callosum appears in patients with amyotrophic lateral sclerosis (ALS) before clinical signs of upper motor neuron death. Considering the ALS-associated impairment of astrocytic glutamate uptake, we have characterized the expression and activity of the glutamate transporter isoforms GLT-1a and GLT-1b in the corpus callosum of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A)). We have also studied the effect of peptide histidine isoleucine (PHI), a vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 2 (VPAC(2)) agonist on glutamate transporters both in vivo and in callosal astrocytes. Before the onset of motor symptoms, the expression of both transporter isoforms was correlated with a constitutive activity of caspase-3. This enzyme participates in the down-regulation of GLT-1 in ALS, and here we demonstrated its involvement in the selective degradation of GLT-1a in the white matter. A single stereotactic injection of PHI into the corpus callosum of symptomatic rats decreased caspase-3 activity and promoted GLT-1a expression and uptake activity. Together, with evidence for a reduced expression of prepro-VIP/PHI mRNA in the corpus callosum of transgenic animals, these data shed light on the modulatory role of the VIP/PHI system on the glutamatergic transmission in ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Biological Transport; Caspase 3; Corpus Callosum; Excitatory Amino Acid Transporter 2; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glutamates; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; Peptide PHI; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Superoxide Dismutase; Superoxide Dismutase-1; Vasoactive Intestinal Peptide

Autoimmune dysfunction of endogenous vasoactive neuropeptides (VNs) such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) has been postulated as a cause for some fatigue-related conditions. VN receptors are class II G protein-coupled receptors (GPCRs) which couple primarily to the adenylate cyclase (AC)-cyclic AMP (cAMP) pathway and cAMP has a central role in neurological metabolism including influencing blood-brain barrier (BBB) and blood-spinal barrier (BSB) permeability, coordinating neuroregulatory pathways, and protecting against neuronal apoptosis. Complex clinical signs occur in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While traditionally viewed as diseases of the motor system, the clinical picture of these conditions is considerably more complex. Disturbances of cognition and memory, as well as emotional lability occur along with fatigue and motor dysfunction. This paper explores the hypothesis that autoimmune dysfunction of VNs may contribute to MS and ALS. While MS and ALS differ in important respects, they have common pathogenic features including inflammation, oxidative stress and mitochondrial dysfunction. Apoptotic mechanisms are associated with activation of caspase pathways and functional interplay between proinflammatory cytokines, interferon gamma and nitric oxide is suggested associated with oxidative stress and glial activation. Diseases such as MS and ALS may represent related conditions resulting from variation in expression of different receptor subtypes of the VN family. Anatomical differences of these receptors, perhaps in areas overly dependent on a specific VN receptor sub-type, may predispose to autoimmune susceptibility to these conditions, either in impaired expression of receptors or antibody and cellular immune targeting of them. Further studies are required to determine if such VN receptor sub-types of significant specificity exist and if they are susceptible to compromise. This hypothesis, if proven, may have implications for the development of treatment and preventive strategies.

Topics: Amyotrophic Lateral Sclerosis; Humans; Models, Immunological; Multiple Sclerosis; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, G-Protein-Coupled; Vasoactive Intestinal Peptide

In 10 patients with amyotrophic lateral sclerosis (ALS), the CSF content of the neuropeptides vasoactive intestinal polypeptide (VIP) and cholecystokinin (CCK) as well as neural cell adhesion molecule (NCAM) was investigated. Compared with normal controls, no deviations were found in CCK or NCAM, while the values of VIP were significantly lower in ALS patients. This finding may reflect a loss of motor neurons.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antigens, Surface; Bulbar Palsy, Progressive; Cell Adhesion Molecules; Cholecystokinin; Female; Humans; Male; Middle Aged; Muscular Atrophy; Vasoactive Intestinal Peptide