The Involvement of Insulin-Like Growth Factor 1 and Nerve Growth Factor in Alzheimer’s Disease-Like Pathology and Survival Role of the Mix of Embryonic Proteoglycans: Electrophysiological Fingerprint, Structural Changes and Regulatory Effects on Neurotrophins

Alzheimer’s disease (AD)-associated neurodegeneration is triggered by different fragments of amyloid beta (Aβ). Among them, Aβ (25-35) fragment plays a critical role in the development of neurodegeneration—it reduces synaptic integrity by disruption of excitatory/inhibitory ratio across networks and alters the growth factors synthesis. Thus, in this study, we aimed to identify the involvement of neurotrophic factors—the insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF)—of AD-like neurodegeneration induced by Aβ (25-35). Taking into account our previous findings on the neuroprotective effects of the mix of proteoglycans of embryonic genesis (PEG), it was suggested to test its regulatory effect on IGF-1 and NGF levels. To evaluate the progress of neurodegeneration, in vivo electrophysiological investigation of synaptic activity disruption of the entorhinal cortex–hippocampus circuit at AD was performed and the potential recovery effects of PEG with relative structural changes were provided. To reveal the direct effects of PEG on brain functional activity, the electrophysiological pattern of the single cells from nucleus supraopticus, sensomotor cortex and hippocampus after acute injection of PEG was examined. Our results demonstrated that after i.c.v. injection of Aβ (25-35), the level of NGF decreased in cerebral cortex and hypothalamus, and, in contrast, increased in hippocampus, prompting its multidirectional role in case of brain damage. The concentration of IGF-1 significantly increased in all investigated brain structures. The administration of PEG balanced the growth factor levels accompanied by substantial restoration of neural tissue architecture and synaptic activity. Acute injection of PEG activated the hypothalamic nucleus supraopticus and hippocampal neurons. IGF-1 and NGF levels were found to be elevated in animals receiving PEG in an absence of amyloid exposure. We suggest that IGF-1 and NGF play a critical role in the development of AD. At the same time, it becomes clear that the neuroprotective effects of PEG are likely mediated via the regulation of neurotrophins.

Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors

Bradykinin (BK) and des-Arg9-BK are pro-inflammatory mediators acting via B2 (B2R) and B1 (B1R) receptors, respectively. We investigated the role of B2R and B1R in lipopolysaccharide (LPS)-induced hypothalamo-pituitary-adrenal (HPA) axis activation in SD rats. LPS given intraperitoneally (ip) up-regulated B1R mRNA in the hypothalamus, both B1R and B2R were up-regulated in pituitary and adrenal glands. Receptor localization was performed using immunofluorescence staining. B1R was localized in the endothelial cells, nucleus supraopticus (SON), adenohypophysis and adrenal cortex. B2R was localized nucleus paraventricularis (PVN) and SON, pituitary and adrenal medulla. Blockade of B1R prior to LPS further increased ACTH release and blockade of B1R 1 h after LPS decreased its release. In addition, we evaluated if blockade of central kinin receptors influence the LPS-induced stimulation of hypothalamic neurons. Blockade of both B1R and B2R reduced the LPS-induced c-Fos immunoreactivity in the hypothalamus. Our data demonstrate that a single injection of LPS induced a differential expression pattern of kinin B1R and B2R in the HPA axis. The tissue specific cellular localization of these receptors indicates that they may play a crucial role in the maintenance of body homeostasis during endotoxemia.

Morphologie und Dysfunktion hypothalamischer Substrukturen bei affektiven Störungen

ZusammenfassungDie Bedeutung des Hypothalamus für die Physiologie der Affektregulation erwächst aus der Beteiligung einzelner Kerngebiete an der Regulation von Stimmung, Antrieb und Wachheit. Dabei gelangen kortikale Afferenzen über limbische Strukturen wie Amygdala und Hippocampus zu hypothalamischen Substrukturen. Diese wiederum senden Efferenzen unter Aufnahme parasympathischer und sympathischer Fasern in die Körperperipherie. Durch den dorsalen Vaguskern vermittelt können hypothalamische Kerngebiete einen regulatorischen Einfluss auf autonome Funktionen ausüben. In Post-mortem-Studien fand sich bei Patienten mit affektiven Störungen gegenüber Kontrollen eine Volumenreduktion des Hypothalamus, die unter anderem als ein neurobiologisches Korrelat einer Dysregulation der Hypothalamus-Hypophysen-Nebennierenrinden-Achse gewertet wurde. Hypothalamische Substrukturen wie der laterale Hypothalamus sowie die supraoptische Region (Nucleus suprachiasmaticus, Nucleus supraopticus) sind aufgrund ihrer kortikolimbischen und mesenzephalen Afferenzen und Efferenzen in besonderer Weise in die Regulation von Wachheit und Emotionen eingebunden. Aufgrund der Stellung hypothalamischer Kerngebieten zwischen kortikalen und limbischen Afferenzen sowie sympathischen-parasympathischen Efferenzen spielt der Hypothalamus eine wesentliche Rolle in einem neuroanatomischen Modell affektiver Funktionsstörungen, das in der vorliegenden Übersichtsarbeit vorgestellt wird.

QUANTITATIVE HISTOCHEMISTRY OF HYPOTHALAMUS II. THIAMINE PYROPHOSPHATASE, NUCLEOSIDE DIPHOSPHATASE AND ACID PHOSPHATASE IN THE ACTIVATED SUPRAOPTIC NUCLEUS OF THE RAT

The activities of nucleoside diphosphatases and thiamine pyrophosphatase (TPPase) that are associated with the Golgi apparatus and acid phosphatase were measured by quantitative histochemical methods both in histologically pure nucleus supraopticus and in an adjacent area of the anterior hypothalamus of the rat. In the nucleus supraopticus UDP-phosphohydrolase (UDPase), GDP-phosphohydrolase (GDPase) and TPPase activities increased 40% after a thirsting period of 3 days, while IDP-phosphohydrolase activity increased 18% and acid phosphatase activity decreased 25% after the same osmostic stress. The adjacent, nonsupraoptic anterior hypothalamic area did not show significant changes in activity of any of the enzymes studied. The activities of the Golgi-associated TPPase, UDPase and GDPase are likely to be reliable parameters for neurosecretory activity.

THE QUANTITATIVE HISTOCHEMISTRY OF HYPOTHALAMUS I. PENTOSE SHUNT ENZYMES IN THE ACTIVATED SUPRAOPTIC NUCLEUS OF THE RAT

The activities of two enzymes involved in the oxidative part of the pentose cycle and one glycolytic enzyme have been measured by quantitative histochemical methods both in histologically pure nucleus supraopticus and in an adjacent area of the anterior hypothalamus of rat. In the nucleus supraopticus, glucose 6-phosphate dehydrogenase activity increased 34% and 6-phosphogluconate dehydrogenase activity declined by 9%, while lactic dehydrogenase activity did not change significantly after a thirsting period of 6 days. The nonsupraoptic, adjacent anterior hypothalamic area did not show significant changes in activity of any of the enzymes studied.