Depression is a multicausal disorder and has been associated with the risk to develop cancer, dementia, diabetes, epilepsy and stroke. As a metabolic disorder depression has been associated with obesity, diabetes, insulin sensitivity, neuropeptide Y, glucose regulation, poor glycemic control, glucagone-like peptide-1, cholezystokinin, ghrelin, leptin, the endocannabinoid system, insulin-like growth factor and gastrin-releasing peptide. As a cardiovascular disease a close relationship exists between depression and blood pressure, heart rate, norepinephrine, sympathetic tone, vascular resistance, blood viscosity, plasma volume, intima thickness and atherosclerosis. Additionally blood coagulation, fibrinolysis, D-dimers, plasminogen activator inhibitor-1 protein, platelet activation, VEGF, plasma nitric oxide and its synthase are changed in depressed patients. As an endocrinological and stress disorder depression has been connected with the concentration of free T4, TSH, CRH, arginine vasopressin, corticotrophin, corticosteroid release and ACTH. Depression as an inflammatory disorder is mediated by pro-inflammatory cytokines, interleukin-1, interleukin-6, TNF-alpha, soluble interleukin-2 receptors, interferon-alpha, interleukin 8, interleukin-10, hs-CRP, acute phase proteins, haptoglobin, toll like receptor 4, interleukin-1beta, mammalian target of rapamycin pathway, substance P, cyclooxygenase-2, prostaglandin-E2, lipid peroxidation levels and acid sphingomyelinase. Nutritional factors might influence depression risk, i.e. the consumption of folate, omega-3 fatty acids, monounsaturated fatty acids, olive oil, fish, fruits, vegetables, nuts, legumes, vitamin B6 and vitamin B12. The neurodegenerative hypothesis of depression explains decreased hippocampal volumes in depressed patients and changes of neurotrophic support by BDNF, erythropoietin, GDNF, FGF-2, NT3, NGF and growth hormone. In this context, a fast neuroprotective and antidepressant effect has also been observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications.

/pdf/molecular-mechanisms-of-depression-perspectives-on-new-51kg9254ke.pdf

Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies

Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target

Neuroinflammation in Alzheimer's disease: Current evidence and future directions

The results of neural tracing studies suggest that vagal afferent fibers in cervical and thoracic branches innervate the esophagus, lower airways, heart, aorta, and possibly the thymus, and via abdominal branches the entire gastrointestinal tract, liver, portal vein, billiary system, pancreas, but not the spleen. In addition, vagal afferents innervate numerous thoracic and abdominal paraganglia associated with the vagus nerves. Specific terminal structures such as flower basket terminals, intraganglionic laminar endings and intramuscular arrays have been identified in the various organs and organ compartments, suggesting functional specializations. Electrophysiological recording studies have identified mechano- and chemo-receptors, as well as temperature- and osmo-sensors. In the rat and several other species, mostly polymodal units, while in the cat more specialized units have been reported. Few details of the peripheral transduction cascades and the transmitters for signal propagation in the CNS are known. Glutamate and its various receptors are likely to play an important role at the level of primary afferent signaling to the solitary nucleus. The vagal afferent system is thus in an excellent position to detect immune-related events in the periphery and generate appropriate autonomic, endocrine, and behavioral responses via central reflex pathways. There is also good evidence for a role of vagal afferents in nociception, as manifested by affective-emotional responses such as increased blood pressure and tachycardia, typically associated with the perception of pain, and mediated via central reflex pathways involving the amygdala and other parts of the limbic system. The massive central projections are likely to be responsible for the antiepileptic properties of afferent vagal stimulation in humans. Furthermore, these functions are in line with a general defensive character ascribed to the vagal afferent, paraventricular system in lower vertebrates.

Functional and chemical anatomy of the afferent vagal system.

Cytokine-induced sickness behaviour: mechanisms and implications.

Oxytocin may mediate the benefits of positive social interaction and emotions

Intravenous administration of interleukin-1 (IL-1) activates central autonomic neuronal circuitries originating in the nucleus of the solitary tract (NTS). The mechanism(s) by which blood-borne IL-1 regulates brain functions, whether by operating across the blood-brain barrier and/or by activating peripheral sensory afferents, remains to be characterized. It has been proposed that vagal afferents originating in the periphery may monitor circulating IL-1 levels, because neurons within the NTS are primary recipients of sensory information from the vagus nerve and also exhibit exquisite sensitivity to blood-borne IL-1. In this study, we present evidence that viscerosensory afferents of the vagus nerve respond to intravenously administered IL-1beta. Specific labeling for mRNAs encoding the type 1 IL-1 receptor and the EP3 subtype of the prostaglandin E2 receptor was detected in situ over neuronal cell bodies in the rat nodose ganglion. Moreover, intravenously applied IL-1 increased the number of sensory neurons in the nodose ganglion that express the cellular activation marker c-Fos, which was matched by an increase in discharge activity of vagal afferents arising from gastric compartments. This response to IL-1 administration was attenuated in animals pretreated with the cyclooxygenase inhibitor indomethacin, suggesting partial mediation by prostaglandins. In conclusion, these results demonstrate that somata and/or fibers of sensory neurons of the vagus nerve express receptors to IL-1 and prostaglandin E2 and that circulating IL-1 stimulates vagal sensory activity via both prostaglandin-dependent and -independent mechanisms.

https://www.jneurosci.org/content/jneuro/18/22/9471.full.pdf

Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins.

The response of mass activity of the gastric vagal afferent nerve to intravenous administration of interleukin-1β (IL-1β) and the involvement of cholecystokinin (CCK) in the response were investigated in pentobarbital-anesthetized rats. Intravenous administration of 2 μg·kg−1 of IL-1β caused an increase in the afferent activity, which reached 150% of control activity by 30 min after administration and persisted for more than 80 min. The increase in the nerve activity was significantly reduced in animals pretreated with a type A CCK receptor antagonist. IL-1β also significantly increased the CCK concentration in systemic blood. Furthermore, it was confirmed that intravenous administration of CCK produced an increase in the nerve activity via the type A CCK receptor. These findings suggest that systemically applied IL-1β increases CCK concentration in systemic blood secreted from mucosal endocrine cells of the small intestine, and that in turn CCK in the gastric blood flow augments or partly participates in the IL-1β-induced excitation of the gastric vagal afferent nerve via stimulation of the type A CCK receptor in the stomach. A possible involvement of IL-1-related excitation of the gastric vagal afferent nerve in IL-1-induced anorexia is discussed.

Interleukin-1 increases activity of the gastric vagal afferent nerve partly via stimulation of type A CCK receptor in anesthetized rats

Changes in cerebral blood flow do not directly affect in vivo recovery of extracellular lactate through microdialysis probe.

Endothelin-1-Induced Lesions in the Brain as a New Model of Focal Ischemia

Thermogenic Action of Capsaicin and Its Analogs

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