1. Effects of endokinin A/B and endokinin C/D on the antinociception properties of hemopressin in mice
Xiaoli Li,Qiaoying Jin,Li Zhao,Yinliang Yang,Lanxia Zhou,Zhengkun Liu,Shouliang Dong Peptides . 2012 Nov;38(1):70-80. doi: 10.1016/j.peptides.2012.08.006.
The current study evaluated the effects of hemopressin (HP) on pain modulation by endokinin A/B (EKA/B) and endokinin C/D (EKC/D) at the supraspinal level in mice. Intracerebroventricular administration of HP (10 nmol) fully antagonized the hyperalgesia induced by EKA/B (10, 30, and 100 pmol), and induced a dose-dependent potent analgesic effect. HP at different concentrations (10 pmol, 100 pmol, and 1 nmol) showed varying effects on the analgesic effect of EKA/B (3 nmol). HP extended the duration of the analgesic effect of EKC/D (3 nmol). Moreover, HP at different concentrations (10 pmol, 5 pmol, 1 pmol, and 100 fmol) co-administered with EKC/D (30 pmol) induced significant analgesia at two different time points: 5 min and 50 min. To investigate the antinociceptive mechanism, we used SR140333B and SR142801. HP (1 pmol) potentiated the analgesic effect of SR140333B (100 pmol)+EKA/B (30 pmol) in 5-10 min, while HP (100 pmol) had no effect in the analgesia induced by SR140333B (3 nmol)+EKA/B (3 nmol). HP (1 nmol) fully inhibited the analgesic effect of SR140333B (3 nmol)+EKC/D (3 nmol) or SR142801 (3 nmol)+EKC/D (3 nmol). HP (1 pmol) weakened the analgesic effect of SR142801 (100 pmol)+EKA/B (30 pmol), but HP (100pmol) strengthened the analgesic effect of SR142801 (3 nmol)+EKA/B (3 nmol). These findings may pave the way for a new strategy on investigating the interaction between tachykinins and opioids on pain modulation.
2. VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects
Dan Chen,Kangtai Xu,Xiaoyu Zhang,Jian Xiao,Ning Li,Mengna Zhang,Qinqin Zhang,Biao Xu,Hanwen Zhu,Quan Fang,Run Zhang,Jiandong Niu,Ting Zheng Neuropharmacology . 2020 Sep 15;175:108178. doi: 10.1016/j.neuropharm.2020.108178.
Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(α) (VD-Hpα) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF1or NPFF2receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF1and NPFF2receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpα-NH2induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH2and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.
3. Further Characterization of Hemopressin Peptide Fragments in the Opioid and Cannabinoid Systems
Ferenc Zador,Engin Bojnik,Anna Borsodi,Eszter Szlavicz,Zsuzsanna Helyes,Csaba Tomboly,Pannilage Shiromi Perera,Sandor Benyhe Anesth Analg . 2015 Dec;121(6):1488-94. doi: 10.1213/ANE.0000000000000964.
Background:Hemopressin, so-called because of its hypotensive effect, belongs to the derivatives of the hemoglobin α-chain. It was isolated from rat brain membrane homogenate by the use of catalytically inactive forms of endopeptidase 24.15 and neurolysin. Hemopressin has antihyperalgesic features that cannot be prevented by the opioid receptor antagonist, naloxone.Methods:In the present study, we investigated whether hemopressin (PVNFKFLSH) and its C-terminally truncated fragment hemopressin 1-7 (PVNFKFL) have any influence on opioid-dependent signaling. Peptides have been analyzed using G-protein-stimulating functional and receptor bindings in this experimental setup.Results:These 2 compounds efficiently activated the G-proteins, and naloxone slightly blocked this stimulation. At the same time, they were able to displace radiolabeled [3H]DAMGO, a selective ligand for μ-opioid system, at micromolar concentrations. Displacement caused by the heptapeptide was more modest compared with hemopressin. Experiments performed on cell lines overexpressing μ-opioid receptors verified the opioid activity of both hemopressins. Moreover, the CB1 cannabinoid receptor antagonist, AM251, significantly decreased their G-protein stimulatory effect.Conclusions:Here, we further confirm that hemopressins can modulate CB1 receptors and can have a slight modulatory effect on the opioid system.
4. Effect of (m)RVD-hemopressin against Aβ1-42-induced apoptosis and inhibition of neurite outgrowth in SH-SY5Y cells
Jieyuan Zhang,Fengrui Hu,Jiaming Lv,Jing Luan,Kang Li,Peng Chen,Huifang Guo,Ruisan Zhang,Yuelin Zhang,Qiang Cai,Xingchun Gou,Jianghong Cheng Neuropeptides . 2020 Jun;81:102044. doi: 10.1016/j.npep.2020.102044.
Alzheimer's disease (AD) is a serious neurodegenerative disease. Senile plaques (SPs) in the extracellular space and neurofibrillary tangles (NFTs) in the intracellular areas of the brain are two typical features of AD. SPs and NFTs are composed of amyloid-β (Aβ) aggregates and hyperphosphorylated Tau, respectively. (m)RVD-hemopressin (RVD), which is derived from mouse brain peptide, binds to the cannabinoid 1 receptor (CB1R) as an agonist. Our previous study indicated that RVD reversed Aβ1-42-induced memory impairment in mice. Here, we investigated the underlying molecular mechanism of RVD on Aβ1-42-induced neurotoxicity in retinoic acid-differentiated human neuroblastoma SH-SY5Y cells. Cell viability and neurite outgrowth were investigated by live cell imaging and analysis instrument. We found that RVD reversed Aβ1-42-induced Tau phosphorylation, apoptosis and suppression of neurite outgrowth and the synapse-associated protein postsynaptic density protein 95 (PSD-95) by inhibiting the activity of protein kinase A (PKA) and glycogen synthase kinase 3β (GSK-3β). Combined treatment with AM251 (a CB1R antagonist) blocked the effects of RVD. In conclusion, RVD may be a potential therapeutic agent for the treatment of cognitive dysfunctions, such as Alzheimer's disease.
