Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the protective properties of peptides related functionally and/or structurally to vasoactive intestinal peptide (VIP), PC12 cultures were treated with iodoacetate as a model for neuronal ischemic/hypoxic injury. Brain tissue can be pre-conditioned against lethal ischemia by several mechanisms including sub-lethal ischemia, moderate hypoglycemia, heat shock, and growth factors. In the present study, a superactive VIP lipophilic analog (Stearyl-Norleucine17-VIP; SNV) was used to pre-condition media of PC12 cells. After removal of the conditioned media, the cultures were exposed to iodoaceate, which inhibits glycolysis. Protective efficacy against iodoacetate-induced injury was assessed by the measurements of lactate dehydrogenase (LDH) activity in the media. Treatment with iodoacetate for 2.5 h produced a twofold increase in LDH activity in the media. The protective effect of SNV had an EC50 of 1 pM. Comparison of the preconditioning time required for full protection by SNV showed no apparent difference between a 15 min and a 2 h incubation period prior to the addition of iodoacetate. Iodoacetate treatment produced a 20% decrease in the RNA transcripts encoding activity-dependent neuroprotective protein (ADNP), a novel glia-derived protein that is regulated by VIP. The iodoacetate-associated reduction in ADNP mRNA was prevented by pre-treatment with SNV. These effects imply that SNV provides a regulatory mechanism for ADNP synthesis during glycolytic stress. Furthermore, a short exposure to SNV provided potent protection from iodoacetate-induced toxicity suggesting that SNV may have therapeutic value in the treatment of ischemic/hypoxic injury.
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PMID:VIP-Related protection against lodoacetate toxicity in pheochromocytoma (PC12) cells: a model for ischemic/hypoxic injury. 1130 79

Pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and peptide histidine-isoleucine (PHI) belong to a structurally related family of polypeptides present in many regions of the central and peripheral nervous system. The neuroprotective potential of PACAP, VIP, and PHI has become a matter of intensive investigations in many animal models. In vitro studies revealed that PACAP protects neurons against apoptosis occurring naturally during CNS development and apoptosis induced by a series of neurotoxins, such as ethanol, hydrogen peroxide (H2O2), prion protein, beta-amyloid, HIV envelope glycoprotein (gp120), potassium ion deficit, and high glutamate concentrations. Similarly, in vivo investigations conducted in models of ischemia and Parkinson's disease confirmed the neuroprotective properties of PACAP. It was revealed that the anti-apoptotic action of PACAP can be directly associated with the activation of signal transduction pathways preventing apoptosis in neurons or involve glial cells capable of releasing other neuroprotective factors affecting neurons. In contrast to PACAP, the neuroprotective action of VIP depends mainly on stimulation of astrocytes to produce and secrete factors of extremely high neuroprotective potential, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP). It was shown that ADNF and ADNP, as well as their shortened derivatives ADNF-9 and NAP, prevent neurons from electrical blockade, excitotoxicity, apoE deficiency, glucose deficit, ischemia, toxic action of ethanol, beta-amyloid, and gp120. The neuroprotective potential of PHI has not been as thoroughly investigated yet, but recent data have confirmed that this peptide can also function as a neuroprotectant. It is thought that PACAP, VIP, and possibly PHI may serve as a goal of modern therapeutic strategies in various neurodegenerative disorders.
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PMID:[Neuroprotective role of PACAP, VIP, and PHI in the central nervous system]. 1557 49

Pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI), are structurally related endogenous peptides widely expressed in the central and peripheral nervous system and showing rich profile of biological activities. They act as neurotransmitters, neuromodulators and neurotrophic factors. Recently, their neuroprotective potential has been revealed in numerous in vitro and in vivo models. Thus, PACAP and VIP protected the cells from neurotoxic effects of ethanol, hydrogen peroxide (H2O2, beta-amyloid and glycoprotein 120 (gp120). Moreover, PACAP showed neuroprotection against glutamate, human prion protein fragment 106-126 [PrP(106-126)] and C2-ceramide. Both peptides reduced brain damage after ischemia and ameliorated neurological deficits in a model of Parkinson's disease. Neuroprotective potential of PHI has not been thoroughly investigated yet, but several results obtained in the last years do not exclude it. The mechanism underlying neuroprotective properties of PACAP seems to involve activation of adenylyl cyclase (AC) --> cyclic adenosine 3',5'-mono-phosphate (cAMP) --> protein kinase A (PKA) and mitogen-activated protein (MAP) kinase pathways, and inhibition of caspase-3. PACAP can also, yet indirectly, stimulate astrocytes to release neuroprotective factors, such as regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein 1 (MIP-1) chemokines. Neuroprotective activity of VIP seems to involve an indirect mechanism requiring astrocytes. VIP-stimulated astrocytes secrete neuroprotective proteins, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP), as well as a number of cytokines. However, in the activated microglia, VIP and PACAP are capable of inhibiting the production of inflammatory mediators which can lead to neurodegenerative processes within the brain. In conclusion, studies carried out on the central nervous system have shown that PACAP, VIP, and likely PHI, are endowed with a neuroprotective potential, which renders them (or their derivatives) promising therapeutic agents in several psychoneurological disorders linked to neurodegeneration.
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PMID:Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. 1598 13

Perinatal asphyxia is an important cause of neonatal mortality and subsequent serious sequelae such as motor and cognitive deficits and seizures. Recent studies have demonstrated that short peptides derived from activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP) are neuroprotective at femtomolar concentrations. However, the effect of these peptides on the hypoxic-ischemic brain injury model is unknown. The aim of this study is to investigate the effects of the peptides ADNF-9 and NAP on neurodegeneration and cerebral nitric oxide (NO) production in a neonatal rat model of hypoxic-ischemic brain injury. Seven-day-old Wistar Albino rat pups have been used in the study (n=42). Experimental groups in the study were: sham-operated group, ADNF-9-treated hypoxia-ischemia group, NAP-treated hypoxia-ischemia group, ADNF-9+NAP-treated hypoxia-ischemia group, and vehicle-treated group. In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. ADNF-9, NAP, and ADNF-9+NAP were injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Brain nitrite levels, neuronal cell death, and apoptosis were evaluated in both hemispheres (carotid ligated or nonligated) 72 h after the hypoxic-ischemic insult. Histopathological evaluation demonstrated that ADNF-9 and NAP significantly diminished number of "apoptotic cells" in the hippocampal CA1, CA2, CA3, and gyrus dentatus regions in both hemispheres (ligated and nonligated). When compared with vehicle-treated group, combination treatment with ADNF-9+NAP did not significantly reduce "apoptotic cell death" in any of the hemispheres. ADNF-9 and NAP, when administered separately, significantly preserved the number of neurons CA1, CA2, CA3, and dentate gyrus regions of the hippocampus, when compared with vehicle-treated group. The density of the CA1, CA2, and dentate gyrus neurons was significantly higher when combination therapy with ADNF-9+NAP was used in the carotid ligated hemispheres. In the nonligated hemispheres, combination therapy preserved the number of neurons only in the CA1 and dentate gyrus regions. Brain nitrite levels were evaluated by Griess reagent and showed that hypoxic-ischemic injury caused a significant increase in NO production. Brain nitrite levels in ADNF-9+NAP-treated animals were not different in carotid ligated or nonligated hemispheres. The peptides ADNF-9 and NAP significantly decreased NO overproduction in the hypoxic-ischemic hemisphere, whereas no significant change appeared in hypoxia alone and also in the sham-operated group. These results suggest the beneficial neuroprotective effect of ADNF-9 and NAP in this model of neonatal hypoxic-ischemic brain injury. To our knowledge, this is the first study that demonstrates a protective effect of these peptides against hypoxia-ischemia in the developing brain.
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PMID:Neuroprotective effect of the peptides ADNF-9 and NAP on hypoxic-ischemic brain injury in neonatal rats. 1693 77

Allon Therapeutics Inc is developing AL-108, an intranasally administered, eight-amino-acid peptide fragment (known as NAP) of activity-dependent neuroprotective protein, and AL-208, an intravenous formulation of NAP. AL-108 is undergoing phase II trials for cognitive impairment in Alzheimer's disease and schizophrenia. AL-108 is also being investigated as a neuroprotective agent, including for the treatment of Parkinson's disease and ocular disease. AL-208 is undergoing phase II clinical trials for the treatment of cognitive disorder and phase I clinical trials for ocular disease and cognitive deficits associated with coronary artery bypass graft or ischemia.
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PMID:AL-108 and AL-208, formulations of the neuroprotective NAP fragment of activity-dependent neuroprotective protein, for cognitive disorders. 1860 May 85

NAPVSIPQ (NAP), an 8 amino acid peptide derived from activity-dependent neuroprotective protein (ADNP), provides neuroprotection through interaction with microtubules. Previous results have demonstrated NAP protection against oxygen-glucose deprivation in hippocampal cells in culture. Furthermore, in vivo studies have shown that NAP reduces caspase 3 activation in rats subjected to permanent mid-cerebral artery occlusion (a rat model of stroke). Oxygen-glucose deprivation (ischemia) has been associated with microtubule breakdown and cytochrome c release from mitochondria leading to apoptosis. Here, NAP in concentrations ranging from 10(-14)M to 10(-8)M completely blocked cytochrome c release in cortical neurons subjected to oxygen-glucose deprivation. Furthermore, quantitative microscopy coupled to microtubule immunocytochemistry suggested that NAP prevented microtubule degradation under oxidative stress. As cytochrome c release is a known initiator of the apoptotic pathway, it is suggested that NAP inhibits the early events of apoptosis.
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PMID:NAP protects against cytochrome c release: inhibition of the initiation of apoptosis. 1961 22

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a neuroprotective action against ischemic damage. This action is mediated by the interleukin-6 (IL-6) pathway. However, as the expression patterns of PACAP receptors and IL-6 following ischemia are not understood, we evaluated them in the mouse hippocampus in response to ischemia induced by bilateral common carotid artery occlusion. Real-time PCR determination of PAC1R mRNA expression in the hippocampus was significantly elevated on day 7 after ischemia. VPAC1R mRNA expression was significantly decreased 3 days after the ischemic episode, while VPAC2R mRNA expression showed a nonsignificant tendency to increase on day 7. IL-6 mRNA expression was significantly increased on day 3 and peaked on day 7 after ischemia. The mRNA expression of activity-dependent neuroprotective protein, which is a neuroprotective factor stimulated by PACAP, remained virtually unchanged in response to ischemia. IL-6 immunoreactivity was detected in the CA1 pyramidal cell layer and colocalized with the neuronal marker NeuN on day 1 after ischemia. On day 3, irregularly shaped IL-6-immunopositive cells colocalized with the astrocytic marker glial fibrillary acidic protein but not with the microglial marker Iba1. PAC1R immunoreactivity co-labeled with IL-6 immunoreactivity. These results suggest that PACAP could stimulate IL-6 secretion by neurons during the acute phase after an ischemic episode and thereafter by astrocytes during the subacute phase.
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PMID:IL-6 and PACAP receptor expression and localization after global brain ischemia in mice. 2266 9