Regenerative mechanisms often require reemployment of

Regenerative mechanisms often require reemployment of pathways used during development in the embryonic and postnatal periods (Waschek, 2002). PACAP has diverse neurodevelopmental and growth factor-like effects (Botia et al., 2007; Vaudry et al., 2009; Waschek, 2002; Watanabe et al., 2016) and it is upregulated upon numerous harmful stimuli, supporting its endogenous effects in restorative processes (Somogyvari-Vigh and Reglodi 2004; Washek 2002). Therefore, it is not surprising that endogenous and exogenous PACAP has strong neuro- and general cytoprotective effects. PACAP is unique, since, unlike other neuropeptides, such as its structurally closest analogue, vasoactive intestinal polypeptide (VIP), it has a potent triple action of anti-apoptotic, anti-inflammatory and anti-oxidant effect in a broad range of tissues. This exceptional combination of action of PACAP is the rationale for our focus on this neuropeptide, which is evolutionarily conserved and secreted by neurons, endothelial, immune and endocrine CM-272 (Delgado et al., 2003; Ohtaki et al., 2010; Reglodi et al., 2011; Somogyvari-Vigh and Reglodi, 2004; Vaudry et al., 2009). The main signaling route is likely through the protective pathways activated by the PAC1 receptor/PKA and PKC-mediated signaling, leading to a decrease in pro-apoptotic factors (like caspases, cytochrome c, Bad, Bax, JNK, p38 MAPK, apoptosis inducing factor-AIF) and an increase in anti-apoptotic signaling molecules (like Bcl-2, Bcl-xL, extracellular signal regulated kinase-ERK, 14-3-3 protein). The accompanying effect on the anti-inflammatory pathways (decrease of several inflammatory cytokines) and anti-oxidative molecules (increase in astrocytic GSH) help in the neuroprotective effect. In addition, PACAP stimulates the release of other trophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) (Manecka et al., 2016; May et al., 2010; Reglodi et al., 2011, Reglodi et al., 2017; Shioda et al., 2006; Vaudry et al., 2009). The first proof for the neuroprotective effects of PACAP came from cerebellar granule cells exposed to neurotoxicity or serum deprivation (rev.: Somogyvari-Vigh and Reglodi, 2004). Neurotoxic injuries induced by several other neurotoxicants have since been proven to be counteracted by endogenous or exogenous PACAP. The overwhelming evidence for the neuroprotective efficacy of PACAP against neurotoxic insults makes PACAP/PACAP receptor signaling a promising therapeutic approach in neurotoxic injuries. The aim of the present review is to give an overview on the neurotoxic insults against which PACAP has been shown to protect neurons. We summarize findings on the neuroprotective actions of PACAP according to the neurotoxic stimuli. A complex interplay of different mechanisms play a role in multifactorial diseases, such as oxidative stress, inflammation, excitotoxicity are all aggravating factors in stroke, traumatic brain injury or neurodegenerative diseases (Brifault et al., 2016). In the present review we focus on the individual neurotoxic components, not on complex disease mechanisms, in order to provide a summary of factors against which PACAP can be neuroprotective.
Protective effects of PACAP against neurotoxic agents
Conclusions
Conflict of interest
Introduction Antimicrobial peptides (AMP) are an indispensable component of the innate immune system of multicellular animals and plants [1]. Small changes in the amino acid sequence of AMP can sometimes result in very large changes in activity against different microbial species. The clinical use of AMP has been proposed as a strategy to overcome the frequent resistance of many common microbes to conventional antibiotics [2]. The usefulness of AMP as drugs has usually been limited by residual toxicity, host cell inhibition [3], and their short half-life in circulation due to rapid proteolysis and filtration by the kidney. The few AMP that have been approved by the Food and Drug Administration (FDA) are only used for topical applications [2]. Therefore, there is a need for AMP analogs that have fewer impediments in order to effectively treat certain infections. AMP with other useful biological activities, especially potent immunosuppressive or cytoprotective activity, could have a wide range of medical applications [4,5].