The increase in people’s longevity has, consequently, led to more brain involvement and neurodegenerative diseases, which can become complicated and lead to chronic degenerative diseases, thereby presenting greater public health problems. Medicinal plants have been used since ancient times and contain high concentrations of molecules, including polyphenols. It has been proven that polyphenols, which are present in various natural sources can provide curative effects against various diseases and brain disorders through neuroprotective effects. These neuroprotective effects are mainly attributed to their ability to cross the blood–brain barrier, eliminate reactive oxygen species, and cause the chelation of metal ions. Polyphenols increase the concentration of neurotrophic factors and bind directly to the membrane receptors of these neurotrophic factors, to modulate and activate the signaling cascades that allow the plasticity, survival, proliferation, and growth of neuronal cells, thereby allowing for better learning, memory, and cognition. Moreover, polyphenols have no serious adverse side effects resulting from their consumption.

Early life stress (ELS) is a risk factor for the development of chronic diseases resulting from functional alterations of organs in the cardiorespiratory and renal systems. This work studied the changes in oxidative stress enzyme activities (EAs) of SOD, CAT, GPX, GR, GST, NOS, MDA, and FRAP in different organs (heart, liver, kidney, adrenal glands (AGs), and pancreas) of male and female Sprague–Dawley rat pups on postnatal day (PN) 15, immediately after basal and acute or chronic stress conditions were accomplished, as follows: basal control (BC; undisturbed maternal pups care), stress control (SC; 3 h maternal separation on PN15), basal maternal separation (BMS; daily 3 h maternal separation on PN 1-14), and stress maternal separation (SMS; daily 3 h maternal separation on PN 1-14 and 3 h maternal separation on PN15). Acute or long-term stress resulted in overall oxidative stress, increase in EA, and reduced antioxidant capacity in these organs. Some different response patterns, due to precedent SMS, were observed in specific organs, especially in the AGs. Acute stress exposure increases the EA, but chronic stress generates a response in the antioxidant system in some of the organs studied and is damped in response to a further challenge.

Treatment-resistant depression (TRD) affects 20–30% of patients with major depressive disorder and presents a significant clinical challenge due to its biological diversity. This review highlights standard mechanisms that contribute to treatment resistance beyond traditional monoaminergic models. Evidence supports serotonergic dysregulation, including 5-HT1A autoreceptor dysfunction and “serotonin flooding” as well as dopaminergic deficits linked to anhedonia and an imbalance between glutamate and GABA that impair synaptic plasticity. Changes in neurotrophic signaling, such as reduced BDNF and VEGF activity, complicate recovery by limiting neural repair and regeneration. Chronic inflammation and oxidative stress contribute to neuronal dysfunction, while HPA axis dysregulation may exacerbate depressive symptoms and resistance to antidepressants. Emerging evidence suggests that obesity and gut microbiota imbalance reduce the production of short-chain fatty acids by bacteria and increase intestinal permeability, thereby influencing neuroinflammatory and neurochemical processes in TRD. Neuroimaging studies reveal hyperconnectivity within the default mode network and impaired reward circuits, both of which are associated with persistent symptoms and a poor treatment response. By combining evidence on inflammation, oxidative stress, neuroendocrine disturbances, microbiome changes, and brain connectivity issues, this review develops a comprehensive framework for understanding TRD. It emphasizes the importance of biomarker-based subtyping to guide personalized future treatments.