abstracts-VIP related neuroprotection

[Guest guest]

Note-... Good news-research looking at developmental issues. When I

was looking these up I found some really good related abstracts that

I'll post in the next day or two. Something positive for all my friends

interested in research and not rantings.

1-PolyADP-ribosylation is involved in neurotrophic activity.

2-Prevention of alcohol-induced developmental delays and learning

abnormalities in a model of fetal alcohol syndrome.

3-Novel peptides prevent alcohol-induced spatial learning deficits and

proinflammatory cytokine release in a mouse model of fetal alcohol syndrome.

4-The pregnant spontaneously hypertensive rat as a model of asymmetric

intrauterine growth retardation and neurodevelopmental delay.

5-Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth

in rat hippocampal and cortical cultures

6-The influence of the peptide NAP on Mac-1-deficient mice following closed

head injury.

7-Neuroprotective potential of three neuropeptides PACAP, VIP and PHI.

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J Neurosci. 2005 Aug 10;25(32):7420-8.

PolyADP-ribosylation is involved in neurotrophic activity.

Visochek L, Steingart RA, Vulih-Shultzman I, Klein R, Priel E, Gozes I,

Cohen-Armon M.

The Neufeld Cardiac Research Institute, Sackler School of Medicine, Tel-Aviv

University, Tel-Aviv 69978, Israel.

PolyADP-ribosylation is a transient posttranslational modification of

proteins, mainly catalyzed by poly(ADP-ribose)polymerase-1 (PARP-1). This

highly conserved nuclear protein is activated rapidly in response to DNA

nick formation and promotes a fast DNA repair. Here, we examine a possible

association between polyADP-ribosylation and the activity of neurotrophins

and neuroprotective peptides taking part in life-or-death decisions in

mammalian neurons.

The presented results indicate an alternative mode of PARP-1 activation in

the absence of DNA damage by neurotrophin-induced signaling mechanisms.

PARP-1 was activated in rat cerebral cortical neurons briefly exposed to

NGF-related nerve growth factors and to the neuroprotective peptides NAP

(the peptide NAPVSIPQ, derived from the activity-dependent neuroprotective

protein ADNP) and ADNF-9 (the peptide SALLRSIPA, derived from the

activity-dependent neurotrophic factor ADNF)

In addition, polyADP-ribosylation was involved in the neurotrophic activity

of NGF-induced and NAP-induced neurite outgrowth in differentiating

pheochromocytoma 12 cells as well as in the neuroprotective activity of NAP

in neurons treated with the Alzheimer's disease neurotoxin beta-amyloid. A

fast loosening of the highly condensed chromatin structure by

polyADP-ribosylation of histone H1, which renders DNA accessible to

transcription and repair, may underlie the role of polyADP-ribosylation in

neurotrophic activity.

PMID: 16093393 [PubMed - in process]

-------------------------------------

Am J Obstet Gynecol. 2005 Sep;193(3 Pt 2):1028-34.

Prevention of alcohol-induced developmental delays and learning

abnormalities in a model of fetal alcohol syndrome.

Endres M, Toso L, Roberson R, Park J, Abebe D, Poggi S, Spong CY.

Unit on Perinatal and Developmental Neurobiology, National Insitute of Child

Health and Human Development, National Institutes of Health, Bethesda, MD

20892-0925, USA.

OBJECTIVE: Prenatal alcohol exposure results in fetal death and

neurobehavioral complications including learning impairment. Previously

synthetic peptides derived from activity-dependent neurotrophic factor have

been shown to prevent aspects of alcohol-induced damage in pregnancy. The

objective of this work was to evaluate whether activity-dependent

neurotrophic factor-12 could prevent alcohol-induced damage in a model of

fetal alcohol syndrome.

STUDY DESIGN: Using a well-characterized model, C57Bl6/J mice on gestational

day 8 were treated with placebo, alcohol (30% volume/volume alcohol 0.03

mL/kg), alcohol plus activity-dependent neurotrophic factor-12 30 minutes

prior to alcohol, or activity-dependent neurotrophic factor-12 alone. Fetal

death was assessed on gestational day 18 (25 litters were evaluated:

alcohol, n = 5; placebo, n = 9; alcohol plus activity-dependent neurotrophic

factor-12, n = 11). Neonatal behavior tests were performed on postnatal days

1 through 21 with the offspring of 12 dams (alcohol, n = 16; placebo, n =

46; alcohol plus activity-dependent neurotrophic factor-12, n = 23; and

activity-dependent neurotrophic factor-12, n = 35). Adult males were tested

in the water maze for learning assessment and with the hole punch

activity test for exploratory activity. Statistical analysis included

Kruskal-Wallis and analysis of variance.

RESULTS: Fetal death was greater in alcohol (67% +/- 13%) vs placebo (8.4%

+/- 3%, P < .001). Pretreatment with activity-dependent neurotrophic

factor-12 prevented the alcohol-induced fetal death (2.2% +/- 8.1%) with

levels similar to control (P = .12). Alcohol exposure caused a delay in

achieving developmental milestones, with alcohol achieving milestones later

than all other groups (all P < .001). Pretreatment with activity-dependent

neurotrophic factor-12 prevented the alcohol-induced milestone delays. In

the water maze, the placebo learned, decreasing their latency to find

the hidden platform over 70% (P < .01). Alcohol plus activity-dependent

neurotrophic factor-12 also significantly learned, with a learning curve not

different from placebo (all P > .5) and significantly better than alcohol on

days 4, 6, and 7 (all P < .05). Alcohol exposure resulted in significantly

less time in hole punch activity (P < .02) than control. Activity-dependent

neurotrophic factor-12 pretreatment prevented the alcohol-induced decline,

with levels the same as control (P = .1).

CONCLUSION: The novel peptide activity-dependent neurotrophic factor-12

prevents alcohol-induced fetal death and developmental and learning

abnormalities in a model of fetal alcohol syndrome. This demonstrates that a

single treatment with a peptide is efficacious and may be of value in the

prevention of alcohol-induced damage.

PMID: 16157106 [PubMed - indexed for MEDLINE]

-----------------------------------------------

Am J Obstet Gynecol. 2005 Sep;193(3 Pt 1):825-9.

Novel peptides prevent alcohol-induced spatial learning deficits and

proinflammatory cytokine release in a mouse model of fetal alcohol syndrome.

Vink J, Auth J, Abebe DT, Brenneman DE, Spong CY.

Unit on Perinatal and Developmental Neurobiology, National Institute of

Child Health and Human Development, National Institutes of Health, Bethesda,

MD, USA. jyv5y@...

OBJECTIVE: Previously, the novel peptides NAPVSIPQ and SALLRSIPA were shown

to prevent alcohol-induced fetal death and growth abnormalities in a mouse

model of fetal alcohol syndrome. This study evaluated whether these peptides

could prevent long-term alcohol-induced learning abnormalities. In addition,

because specific cytokines are known to effect long-term potentiation, a

model of learning at the molecular level, we studied the effect of these

novel peptides on tumor necrosis factor-alpha, interleukin-6, and

interferon-gamma levels.

STUDY DESIGN: We used a well-characterized mouse model of fetal alcohol

syndrome. Pregnant mice were injected on day 8 with alcohol (0.03 mL/kg) or

placebo. Pretreatment with NAPVSIPQ+SALLRSIPA (20 mug) or placebo was given

30 minutes before alcohol. Embryos were removed after 6 hours, at which time

cytokine, tumor necrosis factor-alpha, interleukin-6, and interferon-gamma

levels were measured with enzyme-linked immunoassays. To test spatial

learning, adult offspring from litters that were treated with alcohol,

control, NAPVSIPQ+SALLRSIPA then alcohol, or NAPVSIPQ+SALLRSIPA alone were

evaluated for latency to find a hidden platform in the water maze.

RESULTS: Alcohol treatment increased tumor necrosis factor-alpha levels

versus control levels (50.0 +/- 3.5 pg/mL vs 32.7 +/- 2.4 pg/mL; P < .001).

NAPVSIPQ+SALLRSIPA pretreatment prevented this increase (39.9 9 +/- 2.8

pg/mL; P </= .01), with levels similar to control (P=.1). Similarly, alcohol

increased interleukin-6 levels versus control levels (22.6 +/- 1.4 pg/mL vs

17.3 +/- 0.6 pg/mL; P < .001), and NAPVSIPQ+SALLRSIPA prevented this

increase (19.1 +/- 1.0 pg/mL; P </= .02), with levels similar to control

levels (P=.2). Interferon-gamma levels were not different among the 3 groups

(alcohol, 14.6 +/- 4.9 pg/mL; control, 17.9 +/- 6.6 pg/mL;

alcohol+NAPVSIPQ+SALLRSIPA, 13.6 +/- 4.9 pg/mL; P=.2).

In the water maze, alcohol-treated groups did not learn over the

7-day trial compared with the control group (P=.001). Groups that were

pretreated with NAPVSIPQ+SALLRSIPA then alcohol learned significantly, which

was similar to the control group. Groups that were treated with only

NAPVSIPQ+SALLRSIPA learned significantly earlier, with the shortest latency

once learning commenced.

CONCLUSION: The peptides, NAPVSIPQ+SALLRSIPA, prevented the alcohol-induced

spatial learning deficits and attenuated alcohol-induced proinflammatory

cytokine increase in a model of fetal alcohol syndrome. This study

demonstrates the peptides' significant in vivo efficacy with long-lasting

effects obtained after prenatal administration.

PMID: 16150281 [PubMed - indexed for MEDLINE]

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Hypertens Pregnancy. 2005;24(3):201-11.

The pregnant spontaneously hypertensive rat as a model of asymmetric

intrauterine growth retardation and neurodevelopmental delay.

Bassan H, Bassan M, Pinhasov A, Kariv N, Giladi E, Gozes I, Harel S.

The Institute for Child Development and Pediatric Neurology, Division of

Pediatrics, Dana Children's Hospital, Tel-Aviv Sourasky Medical Center,

Tel-Aviv, Israel.

Introduction. Hypertension in pregnancy and vascular placental insufficiency

are considered common pathogenic factors in human intrauterine growth

retardation (IUGR). IUGR neonates experience higher mortality, and the

surviving infants have a higher incidence of neurological and intellectual

impairment.

Methods. To mimic this condition, we used pregnant spontaneously

hypertensive rats (SHR) and performed biometric measurements on Embryonic

Day 20, postnatal developmental reflexes, and locomotor activity

evaluations.

Results. SHR fetuses had significant decreased body weight compared to the

Wistar-Kyoto control fetuses (1.51 +/- 0.02 g vs. 2.05 +/- 0.01 g,

respectively; p < 0.0001), and were relatively microcephalic (2.86 +/- 0.04

cm vs. 3.3 +/- 0.03 cm, respectively; p < 0.0001). Their cephalization index

(head circumference/body weight) was increased (1.88 +/- 0.03 vs. 1.62 +/-

0.02, respectively; p < 0.0001), indicating a " brain-sparing " process. The

disproportional ratio indicated that the IUGR type in this model is

asymmetric.

The SHR pups exhibited a significant (p < 0.04) neurodevelopmental delay in

the acquisition of neonatal reflexes (righting, negative geotaxis, placing),

but they spontaneously caught up with the control pups after approximately

10 days. On Day 30, the SHR pups exhibited significantly increased walking

speed and distance and spent less time in quadrant than the controls (p <

0.002). Conclusion.

We speculate that the model of pregnant SHR closely simulate human IUGR

caused by hypertension in pregnancy and should enable investigation of

mechanisms of hypertension-mediated placenta-vascular injury as well as

provide a system for preclinical evaluations of future preventive

neuroprotective treatments.

PMID: 16263593 [PubMed - in process]

---------------------------------------------

J Mol Neurosci. 2005;25(3):225-38.

Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth

in rat hippocampal and cortical cultures.

-Swintosky VL, Gozes I, Brenneman DE, D' MR, Plata-Salaman CR.

CNS Research, & Pharmaceutical Research and Development,

LLC, Spring House, PA 19447-0776, USA. vswintos@...

Activity-dependent neurotrophic factor (ADNF) is a novel, femtomolar-acting,

glial-derived polypeptide (14 kDa) known to protect neurons from a variety

of toxic insults. The active site for ADNF function is localized to a

9-amino-acid stretch (SALLRSIPA; ADNF-9). A few years later, a novel

ADNF-9-like active peptide (NAPVSIPQ or NAP) was identified and shown to be

expressed in the CNS and exhibit an activity profile similar to ADNF-9. Such

studies suggest that ADNF-9 and NAP might function like other known

neurotrophins and play a role in neural development and maintenance.

The purpose of the present studies was to determine if ADNF-9 or NAP affects

neurite outgrowth and synaptogenesis in rat hippocampal and cortical

cultures. Using MAP2-FITC immunofluorescent labeling, we found that ADNF-9

and NAP promoted neurite outgrowth in a concentration-dependent manner, with

maximal activity observed at femtomolar concentrations.

Both peptides stimulated robust outgrowth in hippocampal cells

(approximately 150% of control; p < 0.01) with a modest effect on cortical

cells (approximately 20% of control; p < 0.05) similar to other known growth

factors. However, the outgrowth-promoting effect was abolished in the

absence of serum, suggesting that soluble factors might be necessary for the

neurotrophic activity. Finally, we found that ADNF-9 and NAP increased

synaptophysin expression in both rat hippocampal and cortical cultures.

These results suggest that ADNF-9 and NAP might contribute to neuronal

plasticity associated with development and repair after injury.

PMID: 15800376 [PubMed - indexed for MEDLINE]

----------------------

Peptides. 2005 Aug;26(8):1520-7. Epub 2005 Apr 15.

The influence of the peptide NAP on Mac-1-deficient mice following closed

head injury.

Zaltzman R, androvich A, Trembovler V, Shohami E, Gozes I.

Department of Clinical Biochemistry, Sackler Medical School, Tel Aviv

University, Tel Aviv 69978, Israel.

A single administration of the neuroprotective peptide NAP was previously

shown to protect against death associated with closed head injury (CHI) and

enhance recovery of the surviving mice. The protective effect was

accompanied by down-regulation of the relative mRNA content of the

complement receptor 3 (Mac-1, a marker for inflammation) as measured about a

month after the injury. In contrast, the mRNA transcripts for

activity-dependent neuroprotective protein (ADNP, the NAP containing

protein) were shown to increase 29 days post CHI in the injured hemisphere

of Mac-1 expressing mice.

The present study was set out to investigate: (1) are Mac-1-deficient mice

less susceptible to the adverse outcome of traumatic head injury; (2) does

NAP treatment affect Mac-1-deficient mice subjected to head injury; and (3)

is Mac-1 expression associated with ADNP expression.

Results showed that (1) Mac-1-deficient mice were partially protected

against death associated with severe head injury as compared to Mac-1

expressing mice. (2) Significant protection against death was observed in

NAP-treated mice and an increase in recovery was observed in the NAP-treated

Mac-1 mice 4 weeks after injury. (3) ADNP expression did not change in the

Mac-1-deficient mice following head injury.

Our working hypothesis is that a month following injury, gene expression in

the injured brain is altered and competing proteins are expressed such as

Mac-1 that is associated with inflammation and ADNP that is associated with

neuroprotection. Obviously, this plasticity in gene expression is intimately

interwoven with the genetic background of the animal. NAP treatment tilts

the balance toward neuroprotection.

PMID: 16042992 [PubMed - indexed for MEDLINE]

--------------------------------------------

Pharmacol Rep. 2005 May-Jun;57(3):307-20.

Neuroprotective potential of three neuropeptides PACAP, VIP and PHI.

Dejda A, Sokolowska P, Nowak JZ.

Centre for Medical Biology, Polish Academy of Sciences, Lodowa 106, PL

93-232 Lodz, Poland. adejda@...

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.

Publication Types:

Review

PMID: 15985713 [PubMed - in process]

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