ABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disease and is typically associated with progressive motor and non-motor dysfunctions. Currently, dopamine replacement therapy is mainly used to relieve the motor symptoms, while its long-term application can lead to various complications and does not cure the disease. Numerous studies have demonstrated that many brain-gut peptides have neuroprotective effects in vivo and in vitro, and may be a promising treatment for PD. In recent years, some progress has been made in studies on the neuroprotective effects of some newly-discovered brain-gut peptides, such as glucagon-like peptide 1, pituitary adenylate cyclase activating polypeptide, nesfatin-1, and ghrelin. However, there is still no systematic review on the neuroprotective effects common to these peptides. Thus, here we review the neuroprotective effects and the associated mechanisms of these four peptides, as well as other brain-gut peptides related to PD, in the hope of providing new ideas for the treatment of PD and related clinical research.
ABSTRACT
PURPOSE: To evaluate genes differentially expressed in ovaries from lean (wild type) and obese (ob/ob) female mice and cyclic AMP production in both groups. METHODS: The expression on messenger RNA levels of 84 genes concerning obesity was analyzed through the PCR array, and cyclic AMP was quantified by the enzyme immunoassay method. RESULTS: The most downregulated genes in the Obesity Group included adenylate cyclase-activating polypeptide type 1, somatostatin, apolipoprotein A4, pancreatic colipase, and interleukin-1 beta. The mean decrease in expression levels of these genes was around 96, 40, 9, 4.2 and 3.6-fold, respectively. On the other hand, the most upregulated genes in the Obesity Group were receptor (calcitonin) activity-modifying protein 3, peroxisome proliferator activated receptor alpha, calcitonin receptor, and corticotropin-releasing hormone receptor 1. The increase means in the expression levels of such genes were 2.3, 2.7, 4.8 and 6.3-fold, respectively. The ovarian cyclic AMP production was significantly higher in ob/ob female mice (2,229±52 fMol) compared to the Control Group (1,814±45 fMol). CONCLUSIONS: Obese and anovulatory female mice have reduced reproductive hormone levels and altered ovogenesis. Several genes have their expression levels altered when leptin is absent, especially adenylate cyclase-activating polypeptide type 1. .
OBJETIVO: Avaliar os genes diferencialmente expressos em ovários de camundongos fêmeas magras (tipo selvagem) e obesas (ob/ob) e a produção de AMP cíclico em ambos os grupos. MÉTODOS: A expressão nos níveis de RNA mensageiro de 84 genes relacionados à obesidade foi analisada por PCR Array, e o AMP cíclico foi quantificado por método imunoenzimático. RESULTADOS: Os genes que mais sofreram diminuição da expressão no Grupo Obesidade incluíram o tipo 1 de polipeptídeo ativador da adenilato ciclase, o da somatostatina, da apolipoproteína A4, da colipase pancreática e da beta interleucina 1. A média de redução na expressão desses genes foi de aproximadamente 96, 40, 9, 4,2 e 3,6 vezes, respectivamente. Por outro lado, os genes que mais tiveram aumento na expressão no Grupo Obesidade foram o gene da proteína modificadora da atividade do receptor de calcitonina 3, do proliferador de peroxissomos ativados por proteína alfa, do receptor de calcitonina e do receptor para hormônio liberador de corticotropinas 1. As médias de acréscimo nos níveis de expressão de tais genes foram de 2,3, 2,7, 4,8 e 6,3 vezes, respectivamente. A produção de AMP cíclico ovariana foi significantemente aumentada em camundongos fêmeas ob/ob (2.229±52 fMol) quando comparada ao Grupo Controle (1.814±45 fMol). CONCLUSÕES: Camundongos fêmeas obesas e anovuladoras possuem níveis de hormônio reprodutivo reduzidos e ovulogênese alterada. Vários genes mostram níveis de expressão alterados quando a leptina está ausente, principalmente o tipo 1 de polipeptídeo ativador da adenilato ciclase. .
Subject(s)
Animals , Female , Mice , Anovulation/genetics , Anovulation/metabolism , Cyclic AMP/biosynthesis , Obesity/genetics , Obesity/metabolism , Mice, Inbred C57BL , Mice, ObeseABSTRACT
This study aimed to investigate the effect of pituitary adenylate cyclase-activating peptide (PACAP) on the pacemaker activity of interstitial cells of Cajal (ICC) in mouse colon and to identify the underlying mechanisms of PACAP action. Spontaneous pacemaker activity of colonic ICC and the effects of PACAP were studied using electrophysiological recordings. Exogenously applied PACAP induced hyperpolarization of the cell membrane and inhibited pacemaker frequency in a dose-dependent manner (from 0.1 nM to 100 nM). To investigate cyclic AMP (cAMP) involvement in the effects of PACAP on ICC, SQ-22536 (an inhibitor of adenylate cyclase) and cell-permeable 8-bromo-cAMP were used. SQ-22536 decreased the frequency of pacemaker potentials, and cell-permeable 8-bromo-cAMP increased the frequency of pacemaker potentials. The effects of SQ-22536 on pacemaker potential frequency and membrane hyperpolarization were rescued by co-treatment with glibenclamide (an ATP-sensitive K+ channel blocker). However, neither N(G)-nitro-L-arginine methyl ester (L-NAME, a competitive inhibitor of NO synthase) nor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) had any effect on PACAP-induced activity. In conclusion, this study describes the effects of PACAP on ICC in the mouse colon. PACAP inhibited the pacemaker activity of ICC by acting through ATP-sensitive K+ channels. These results provide evidence of a physiological role for PACAP in regulating gastrointestinal (GI) motility through the modulation of ICC activity.
Subject(s)
Animals , Mice , 8-Bromo Cyclic Adenosine Monophosphate , Cell Membrane , Colon , Cyclic AMP , Glyburide , Interstitial Cells of Cajal , Membranes , NG-Nitroarginine Methyl Ester , Pituitary Adenylate Cyclase-Activating PolypeptideABSTRACT
BACKGROUND: The effect of pituitary adenylate cyclase activating polypeptide (PACAP) during traumatic brain injury (TBI) and whether it can modulate secondary injury has not been reported previously. The present study evaluated the potential protective effects of ventricular infusion of PACAP in a rat model of TBI. METHODS: Male Sprague Dawley rats were randomly divided into 3 treatment groups (n=6, each): sham-operated, vehicle (normal saline)+TBI, and PACAP+TBI. Normal saline or PACAP (1g/5L) was administered intracerebroventricularly 20 minutes before TBI. Right parietal cortical contusion was produced via a weight-dropping method. Brains were extracted 24 hours after trauma. Histological changes in brains were examined by HE staining. The numbers of CD4+ and CD8+ T cells in blood and the spleen were detected via flow cytometry. RESULTS: In injured brain regions, edema, hemorrhage, inflammatory cell infiltration, and swollen and degenerated neurons were observed under a light microscope, and the neurons were disorderly arrayed in the hippocampi. Compared to the sham group, average CD4+ CD8– lymphocyte counts in blood and the spleen were significantly decreased in rats that received TBI+vehicle, and CD4– CD8+ were increased. In rats administered PACAP prior to TBI, damage was attenuated as evidenced by significantly increased CD4+, and decreased CD8+, T lymphocytes in blood and the spleen. CONCLUSION: Pretreatment with PACAP may protect against TBI by influencing periphery T cellular immune function.
ABSTRACT
Objective: To investigate whether pituitary adenylate cyclase-activating polypeptide (PACAP) can modulate the immune function of mouse LPS-stimulated dendritic cells. Methods: DCs were derived from bone marrow of C57BL/6 using rmGM-CSF and rmIL-4, then the DCs were exposed to different stimuli for indicated time periods. The stimulated DCs and their culture supernatant were subjected to ELISA and FACS analysis. The total RNA was extracted from the stimulated DC for RT-PCR and RNase Protection Assay. Results: PACAP significantly inhibited the production of IL-2, IL-12,TNF-α and MIP-2 in LPS-stimulated DCs (P<0. 05,P<0. 01,P<0. 01 ,P<0. 01.respectirely), but the inhibition of LPS-induced IL-6, MIP-1α and MIP-1β production was not apparent. Conclusion: PACAP can negatively modulate the immunity of LPS-stimulated DCs.
ABSTRACT
Objective To observe the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on the expressions of caspase-3 and X-linked inhibitor of apoptosis protein (XIAP) after hypoxic-ischemic brain damage (HIBD) in neonatal rats and to investigate its neuroprotection and effective dose. Methods Sixty neonatal rats were randomly allocated to one of three groups: sham operation, saline control and PACAP groups. The PACAP group was redivided into high (10-8 mol), medium (10-9 mol) and low (10-12 mol) dose groups. An animal model of HIBD was established. Real-time fluorescent quantitative polymerase chain re-action method was used to detect the expressions of caspase-3 mRNA and XIAP mRNA on af-fected side of brain 24 hours after HIBD in neonatal rats, and spectrophotometry was used to detect the activities of caspase-3. Results Twenty-four hours after HIBD, caspase-3 mRNA expression and enzyme activity, as well as XIAP mRNA expression in the saline control group were increased significantly compared to the sham operation group (all P <0.01). Caspase-3 mRNA expression and enzyme activity in all the PACAP groups were significantly lower than those in the saline control group (all P <0.01), while XIAP mRNA expression was significantly higher than that in the saline control group (all P < 0.01 ). Conclusions PACAP may upregu-late XIAP mRNA expression, inhibit caspase-3 mRNA expression and enzyme activity. It has neuroprotective effect on HIBD in neonatal rats, and it is effective with high, medium and low doses.
ABSTRACT
OBJECTIVE: Pituitary adenylate cyclase-activating polypeptide (PACAP), a novel hypothalamic neuropeptide, has been suggested to play a role in ovarian folliculogenesis. The present study evaluated the effect of PACAP on the growth of preantral follicles. METHODS: Preantral follicles were mechanically isolated from ovaries of 21-day-old rats and cultured in groups for 3 days in serum-free medium in the absence or presence of PACAP-38 (10-6 M). RESULTS: Treatment with PACAP-38 resulted in an increase in follicle diameter by 75% whereas treatment with follicle stimulating hormone (FSH) increased follicle diameter by 65%. PACAP-38 treatment enhanced the granulosa cell proliferation as measured by thymidine incorporation analysis. Furthermore, the production of progesterone by cultured granulosa cells and GFSHR-17 cell line was stimulated by PACAP-38. Interestingly, PACAP enhanced FSH action on stimulation of SF-1 and aromatase gene expression. CONCLUSION: The present results demonstrate that PACAP stimulated preantral follicle growth by potentiating proliferation and by stimulating steroidogenesis.
Subject(s)
Animals , Female , Rats , Aromatase , Cell Line , Follicle Stimulating Hormone , Gene Expression , Granulosa Cells , Neuropeptides , Ovarian Follicle , Ovary , Pituitary Adenylate Cyclase-Activating Polypeptide , Progesterone , ThymidineABSTRACT
Objective To investigate the effects of different doses of pituitary adenylate cyclase- activating polypeptide(PACAP)on the functional and morphological outcome in a mice model of Parkinson' s disease(PD)rendered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).Methods Male mice were treated with PACAP 0.02, 0.20 or 2.00 ?g by iv bolus for 7 days after MPTP was administered, and were compared with the saline-treated mice.The immunohistochemistry and Western blot were used to detect the alterations of PD biomarker including tyrosine hydroxylase(TH), dopamine transporter(DAT)and vesicular monoamine transporter2(VAMT2).In addition, monoamine neurotransmitters in the striatum of mice were measured by the high performance liquid chromatography (HPLC).Results TH immunohistochemistry indicated that the number of TH-positive neurons in the substantia nigra was increased in all PACAP-treated mice(PACAP(0.02 ?g/d)group was 93.33?4.87, F=85.85,P
ABSTRACT
No abstract available.
Subject(s)
Female , Ovulation , Pituitary Adenylate Cyclase-Activating PolypeptideABSTRACT
In order to study the expression and the feasibility of scaled production of neuropeptide in the routine expression system such as E.coli with the pituitary adenylate cyclase activating polypep tide(PACAP) as an example, the following experiments were carried out. First, on the basis of the reported amino acid sequence of PACAP, DNA sequence of PACAP w as deduced and six partially complementary oligonucleotide fragments were design ed. The coding region of PACAP was obtained by renaturing the DNA fragments and ligation and identified by DNA sequencing. The coding region of PACAP was cloned into plasmid pGEX-4T-3 and transformed into E.coli BL21(DE3 ). An expression strain BLPACAP was selected. SDS-PAGE analysis revealed that t he GST-PACAP fusion protein was highly expressed and accumulated to about 30% o f the total bacterial proteins. By affinity chromatography, up to 90% GST-PACAP was purified by one step from bacterial lysate. The purified protein could prom ote neurite outgrowth of PC12 cells and the survival of spinal cord neurons.
ABSTRACT
Pituitary adenylate cyclase-activating polypeptide (PA CAP) which belongs to the secretin/glucagon/VIP family has been originally isola ted from the sheep hypothalamus on the basis of its ability to stimulate cAMP fo rmation in culture rat anterior pituitary cells. Post-translational processing of the PACAP precursor generates two biologically active molecular forms, PACAP -38 and PACAP-27. The primary structure of PACAP has been remarkably conserved during evolution. The sequence of PACAP-27 exhibits substantial similarities w ith those of vasoactive intestinal polypeptide (VIP), glucagon and secretin. The gene encoding the PACAP precursor is widely expressed in brain and various peri pheral organs, notably in endocrine glands, gastro-intestinal，uro-genital tra cts and respiratory system. In vivo and in vitro studies have shown that PACAP exhibits multiple activities especially a trophic activity during ontogen esis, notably in the adrenal medulla and the central nervous system. The biologi cal effects of PACAP are mediated through three distinct receptor subtypes which exhibit differential affinities for PACAP and VIP. The PAC1 receptor, which sho ws high selectivity for PACAP, is coupled to several transduction systems. In co ntrast, VPAC1 and VPAC2, which bind with the same affinity for PACAP and VIP, ar e mainly coupled to the adenylyl cyclase pathway. In conclusion, PACAP is neurop eptide, and it functions as a hypothalamic hormone, neurohormone, neuromodulator , vasodilator, neurotransmitter or trophic factor in the brain and the various o rgans.
ABSTRACT
PURPOSE: Pituitary adenylate cyclase-activating polypeptide (PACAP) showed the relaxant effect and distribution patterns in the penile corpus cavernosum. We investigated the presence, distribution, and effects of PACAP-(1-27) in the clitoral cavernosum (CC). MATERIALS AND METHODS: The isometric tension was measured in the strip of rabbit CC. Immunohistochemistry was used to localize PACAP-(1-27) immunoreactivity in nerve fibers in CC. Possible co-localization of the PACAP-(1-27) immunoreactive nerve fiber with other nerve fiber was investigated by application of double immunofluorescent labeling technique using antibody to protein gene product 9.5 (PGP 9.5). Western blotting was used to identify the expression of PACAP-(1-27) protein. RESULTS: The pre-contracted CC smooth muscle strip with phenylephrine was relaxed dose-dependently with PACAP-(1-27). PACAP-(6-27), PACAP-(1-27) receptor antagonist did not affect the PACAP-(1-27) induced relaxant responses. Pre-treatment with Nw- nitro-L-arginine methyl ester (NO synthase inhibitor) did not affect the relaxation induced by PACAP-(1-27). CC was not stained by anti-human PACAP-(1-27) guinea pig polyclonal antibody and the immunoreactivity for anti-human PGP 9.5 mouse monoclonal antibody was observed throught the CC. Western blotting demonstrated the presence of immunoreactive protein band corresponding to 35 KDa PACAP-(1-27). CONCLUSIONS: The present study shows that PACAP-(1-27) has a possible role in the modulation of smooth muscle tone of the CC resulting in erection.
Subject(s)
Animals , Mice , Adenylyl Cyclases , Blotting, Western , Guinea Pigs , Immunohistochemistry , Muscle, Smooth , Nerve Fibers , Phenylephrine , Pituitary Adenylate Cyclase-Activating Polypeptide , RelaxationABSTRACT
Objective To investigate the effects of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor (PACAP-R) on the pathogenesis of psoriasis. Methods The expression of PACAP and PACAP-R in the skin from 10 normal controls, 25 psoriatic lesions and non-lesional skins was measured by immunohistochemical technique. Results The expression of PACAP and PACAP-R was significantly lower in the psoriatic lesional skins than that of the non-lesional skins. The area density and mean absorbance of PACAP and PACAP-R in the lesional skins were significantly lower compared with those in the non-lesional skins (P