Alzheimer's disease (AD) stands as a devastating neurodegenerative disorder, depicted by the relentless erosion of cognitive and memory faculties. Despite relentless research spanning decades, the quest for efficacious disease-modifying therapies remains an ongoing challenge. Recent strides in the realm of molecular neuropharmacology, however, have revealed a number of potential therapeutic targets for AD, instilling a renewed sense of optimism. This comprehensive review navigates the landscape of emerging avenues in the quest to combat AD, shedding light on a diverse array of targets that hold substantial promise. Central to this discourse are novel targets such as beta-secretase (BACE) and gamma-secretase, instrumental in the making of amyloid-beta (Aβ) peptides, the hallmark culprits of AD pathology. Deconstructing the pathological cascade further, the review delves into the intricate involvement of tau protein abnormalities, neuroinflammation cascades, and proteins linked with synaptic dysfunction. Beyond the traditional scope, this review also ventures into the realm of cutting-edge modalities, elucidating the potential of ground-breaking techniques including immunotherapies and microRNA-based interventions. These innovative strategies, harnessing immune modulation and intricate gene regulation, introduce new dimensions to AD therapeutics, providing novel avenues to halt disease progression. A thorough understanding of these emerging therapeutic targets, coupled with in-depth exploration of their underlying mechanisms, sparks a paradigm shift in conceptualizing potent AD interventions. By targeting these prospects, the objective extends beyond mere symptomatic relief, aiming to not just impede disease advancement but also enhance the well-being of patients and caregivers. However, the transition from potential to clinical reality mandates unwavering commitment to rigorous scientific inquiry and meticulous clinical validation. These promising candidates require further scientific scrutiny and systematic trials to establish efficacy, safety, and long-term benefits. Only through such concerted efforts can the transformative potential of these burgeoning therapeutic targets be translated into robust and secure AD treatments.

Background: This study aims to examine the potential neuroprotective effects of flaxseed oil (FSO) on the brain activity of rat pups sired by females intoxicated with aluminum (Al). The brain is known to be particularly vulnerable to the deleterious effects of aluminum, which promotes oxidative stress and neuroinflammation. FSO is a rich source of omega-3 (ω-3) fatty acids (FA), essential components of neuronal membranes and neurotransmission.

Methods: After collecting 36 offspring aged three weeks from a control group and an intoxicated female group that received an intraperitoneal injection of aluminum chloride (AlCl3) (75 mg/kg body weight, twice a week) in the morning for 30 days. Six subgroups of pup rats for each group (n = 6) were used, with control groups having free access to food and water and two experimental groups receiving low and high doses of FSO administered by gavage (0.5 and 2 mL/kg b.wt.). An intoxicated group was also tested with rats receiving low and high FSO concentrations and free access to water. The study appears to focus on the effect of omega-3 in the FSO on the brain's development of young rats a neurobehavioral study was carried out, followed by estimation of prooxidant parameters and neurotransmitter activity of the brain, and a lipid composition was carried out on the brain membrane by gas chromatography-mass spectrometry (GC-MS) analysis.

Results: The FA profile of FSO revealed domination by ω-3 type (86.9%). The 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging capability was found at half maximal inhibitory concentration (IC₅₀) values of 18.12 g/mL. Neurobehavioral experiments showed significant hyperactivity and memory loss in intoxicated young rats, with decreased levels of lipid peroxidation (LPO) and nitric oxide (NO) and a significant increase in acetylcholinesterase (AChE) activity in the brain. However, ameliorative results were found in both concentrations of FSO administration when compared with intoxicated groups. GC-MS analysis of the brain membrane FA profile revealed the presence of elaidic acid in both the AL and AL+FSO. Neurobehavioral experiments showed significant hyperactivity and memory loss in intoxicated young rats, with decreased levels of lipid peroxidation (LPO) and nitric oxide (NO) and a significant increase in acetylcholinesterase (AChE) activity in the brain. However, ameliorative results were found in both concentrations of FSO administration when compared with intoxicated groups. GC-MS analysis of the brain membrane FA profile revealed the presence of elaidic acid in both the AL and AL+FSO” groups. In contrast, only the AL+FSO' group had eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) areas.

Conclusions: Our results suggest that FSO supplementation at low concentrations has neuroprotective effects on developing rat brains, correcting and ameliorating the abnormalities brought on by embryo/fetal aluminum chloride toxicity.

The Notch signaling pathway plays a crucial role in embryonic development as well as in maintaining tissue homeostasis throughout the lifespan of an adult organism. The involvement of this signaling pathway in the development of certain neurodegenerative diseases and other nervous system disorders is known, yet a comprehensive therapy related to the Notch signaling pathway has not been developed. This underscores the importance of further investigating the molecular mechanisms of the Notch signaling pathway. This review explores the molecular mechanisms by which the Notch signaling pathway participates in neurogenesis and neural differentiation. Finally, we discuss the role of Notch in neurodegenerative pathologies and possible therapeutic approaches.

Background: Depression is a multifactorial mood disorder with a high prevalence worldwide. To date, advances in drug discovery have widened therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors. Fluoxetine is the first selective serotonin reuptake inhibitor with a proven clinical efficacy and safety profile. Metformin, a first-line antiglycemic drug, has been shown to have antidepressant effects in patients with type 2 diabetes. However, the effectiveness of the combination of metformin and fluoxetine in the treatment of depression has not been investigated.

Methods: PC12 (rat adrenal pheochromocytoma) cells were subjected to high-level corticosterone (200 μM) and drug administration. Then the cell apoptosis was measured by a flow cytometry assay. The potential mechanism of the combined application of metformin and fluoxetine on PC12 cells was discussed using reactive oxygen species, intracellular Ca²⁺ analysis, immunofluorescence, and Western blotting.

Results: Our results showed that a combination of metformin and fluoxetine decreased apoptosis, the level of reactive oxygen species, and intracellular Ca²⁺ accumulation. Furthermore, the combined administration lowered the P62 protein expression and the autophagosome ratio, while promoting the expression of LC3B (microtubule-associated protein B-light chain 3) proteins.

Conclusions: The combined use of metformin and fluoxetine in PC12 was found to have a protective effect against corticosterone. Mitochondrial apoptosis inhibition, autophagy flux unblocking, and activation of the AMPK (AMP-activated protein kinase)/BDNF (brain-derived neurotrophic factor) pathway may represent new approaches to enhance neuroprotection.

Background: Neuropathic pain (NP) is a complex pain disorder caused by injury or dysfunction of the somatosensory nervous system. This study aimed to investigate the therapeutic effect of ANA-12 (a BNDF (brain-derived neurotrophic factor) inhibitor, N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl) amino] carbonyl] phenyl] benzo [b] thiophene-2-carboxamide, C₂₂H₂₁N₃O₃S, CAS No. 219766-25-3) on NP and its molecular mechanism.

Methods: Rats were set into sham, model and ANA-12 groups (n = 10 mice/group). NP was induced in rats by sciatic nerve ligation. Astrocytes were treated with lipopolysaccharide (LPS, 100 ng/mL), ANA-12 (50 µM) and MHY1485 (10 µmol/L, C₁₇H₂₁N₇O₄, CAS No. 326914-06-1) to explore the role of ANA-12. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed. Rat spinal dorsal horn astrocytes were activated by LPS induction. Then, rats were treated with ANA-12 and mechanistic target of rapamycin (mTOR) agonists. Cell viability was monitored with cell counting kit 8 (CCK8). Immunofluorescence was used to test activated astrocytes and low complexity communications codec (LC3B) expression. Enzyme linked immunosorbent assay (ELISA) was conducted to measure interleukin (IL)-1β, IL-6 and tumour necrosis factor alpha (TNF-α) concentrations. The expression of autophagy and signaling pathway-related proteins and genes was analyzed by western blot and reverse transcription quantitative-polymerase chain reaction (RT-qPCR).

Results: MWT and TWL of NP rats were significantly reduced compared to normal rats. The number of activated astrocytes increased in the spinal cord tissue of NP rats. The concentration of inflammatory factors and the expression of brain-derived neurotrophic factor (BNDF) and its specific receptor tropomyosin-receptor kinase B (TRKB) proteins increased in the spinal cord of NP rats. After ANA-12 treatment, astrocytes cell viability did not change significantly. Interestingly, ANA-12 treatment significantly reduced LPS-induced activation of astrocytes and pro-inflammatory factors compared to NP rats. Meanwhile, BNDF and TRKB proteins expression decreased, and LC3B and Beclin 1 genes and proteins expression increased after ANA-12 treatment in NP rats. mTOR agonists reversed the autophagy-promoting effect of ANA-12.

Conclusions: Many astrocytes were abnormally activated in NP rats. ANA-12 inhibited inflammation and targeted mTOR to promote autophagy and reduce the activation of LPS-induced astrocytes. In summary, ANA-12 can alleviate NP.