Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with widespread expression and general cytoprotective effects, is also involved in aging. Previously, we observed accelerated systemic senile amyloidosis in PACAP knockout (KO) mice. As mice partially lacking PACAP (heterozygous-HZ) show variable symptoms, here we investigated whether HZ mice have accelerated aging, completed with observations in PAC1 receptor KO mice. As we have limited data on qualitative or quantitative changes in the blood of PACAP-deficient mice, we investigated whether these changes could be in the background of the amyloidosis. Routine histological staining was used to examine amyloid deposits, rated on a severity scale 0–3. Blood was collected from PACAP wild type/HZ mice for complete blood analysis. In contrast to receptor KO mice showing no amyloidosis, histopathological analysis revealed severe deposits in PACAP HZ mice, with kidney, spleen, skin, and intestines being most affected. Increased cholesterol, lipoprotein levels, and differences in several blood count parameters were found in HZ mice. In summary, amyloidosis also develops in partial absence of PACAP, in contrast to the lack of its PAC1 receptor. In addition to the earlier identified inflammatory and degenerative disturbances, the alteration in lipid metabolism and bone marrow activity can also be additional factors leading to systemic degenerative processes

Effects of Postnatal Enriched Environment in a Model of Parkinson’s Disease in Adult Rats

Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson’s disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life

Distribution of bioactive factors in human milk samples

Abstract Background Breast milk provides nutrition for infants and also contains a variety of bioactive factors that influence the development of the newborn. Human milk is a complex biological fluid that can be separated into different layers (water phase and lipid phase with its component water and lipid fractions). It can affect the developing human body along the whole length of the gastrointestinal tract, and through the circulation, its factors may reach every organ. Methods In the present study, we analyzed milk samples collected monthly for 6 months from 16 mothers from the 4th week postpartum between 2014 and 2016 in Baranya County, Hungary. The 96 samples provided us information about the fluctuation of certain bioactive factors during the first 6 months of lactation. We investigated with Luminex technology the concentrations of several cytokines (CD40, Flt-3L), chemokines (MCP-1, RANTES, GRO, MIP-1ß, MDC, eotaxin, fractalkine), and epidermal growth factor (EGF). Paired t-tests and one-way ANOVA followed by Bonferroni post-hoc tests were used to compare the data. Results We detected the presence of each bioactive factor in every layer of the milk samples during the first 6 months of breastfeeding in widespread concentration ranges. In the case of GRO, MIP-1ß, MDC, Flt-3L, fractalkine, and eotaxin, the concentrations were constant during the first 6 months of lactation. The water phase of human milk contained higher factor concentrations compared to both fractions of the lipid phase for most factors (except eotaxin and MIP-1ß). The concentrations of CD40, EGF, MCP-1, and RANTES in the first 3 months were significantly different compared to the values detected between 4th and 6th months. In the water phase, the level of MCP-1 was significantly decreased, while all of the other factors increased during the 4th through 6th months. We found significantly higher EGF, GRO, and RANTES levels in the water fraction compared to the lipid fraction of the lipid phase. Conclusions The novel findings of this investigation were the presence of Flt-3L and MDC in all layers of breast milk, and nearly all bioactive factors in the lipid phase. Due to their widespread physiological effects these factors may have an essential role in organogenesis

Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models

Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP