Novel therapeutic strategies and common mechanisms of neurodegenerative diseases

Neuroprotection holds particular significance in neurodegenerative diseases characterized by the death of brain cells. Despite differences in timeframe, location, pathology, and clinical outcomes, common pathophysiological mechanisms may exist, including oxidative stress and excitotoxicity. So far, neuroprotective therapies have yet to demonstrate significant benefits in clinical trials.1 Reasons for past translational failures may involve low experimental study quality, more complex pathophysiology than expected, challenging drug delivery, late intervention, and safety issues. However, recent advances offer renewed hope and potential breakthroughs that could change the treatment landscape in the future. These novel therapeutic strategies will be discussed in this issue of Neuroprotection. Brain-Derived Neurotrophic Factor (BDNF) plays a crucial role in neuroprotection and neuroplasticity, making it a key target in the treatment of neurodegenerative diseases. Enhancing BDNF levels has shown promise in mitigating neuronal loss and improving cognitive function in conditions such as Alzheimer's and Parkinson's diseases. The review by Wang et al. summarized existing findings regarding BDNF expression, metabolism, and signaling pathways in neurodegenerative diseases. The main conclusion emphasized the need for a deeper understanding of BDNF modulation and the development of BDNF-targeted drugs. Intranasal treatment has emerged as a promising approach to deliver therapeutic agents directly to the brain, potentially enhancing efficacy while reducing systemic side effects. Wen and Ren present a comprehensive review of the current research progress on intranasal Parkinson's disease treatment with cells, growth factors, and drugs. This administration route offers the advantages of being noninvasive, convenient, and practical, allowing various therapeutic products to bypass the blood-brain barrier. However, intranasal delivery is not yet widely applied clinically, possibly due to significant anatomical differences in the brain and nasal structures between humans and rodents. Therefore, robust, evidence-based human studies are required to improve clinical success. Emerging research has revealed that angiotensin II type 1 receptors (AT1R) play a pivotal role in neuroprotection. These receptors, traditionally associated with cardiovascular regulation, are now recognized for their potential to protect against neural damage. Huang and Zhang provide a review of the neuroprotective effects of drugs acting on the angiotensin receptor pathway. Although preclinical studies have demonstrated that the neuroprotective effect is independent of the antihypertensive effect, AT1R antagonists (e.g., candesartan, irbesartan, and losartan) can cause blood pressure fluctuations,2 which may introduce outcome bias. Future research should focus on identifying the optimal dose with minimal impact on blood pressure and determining the best timing for administration to maximize the neuroprotective effects of AT1R agents. The gut microbiome has a notable impact on brain function, particularly in the context of stroke. The review by Chen et al. examined 92 articles to explore the relationship between gut microbiota and ischemic stroke in both experimental and human studies. An impressive body of evidence from animal studies indicates that ischemic stroke can induce dysbiosis of the gut microbiota, which, in turn, can exacerbate the ischemic injury. On the other hand, the gut microbiome also plays a crucial role in recovery after stroke. Studies have demonstrated that specific microbial metabolites, such as short-chain fatty acids, can enhance neuroprotective mechanisms and improve functional outcomes. However, the controlled diet and environment in animal studies can complicate the translation of results to humans.3 Therefore, further human research is needed to pave the way for innovative therapeutic interventions. Glutamate is the primary neurotransmitter in the brain, and excessive release of glutamate has been linked to numerous neurodegenerative diseases. Roman and Gonzalez provided a detailed review on the role of ionotropic glutamate receptors (iGluRs) in brain diseases such as stroke, epilepsy, and multiple sclerosis. Notably, recent research has increasingly focused on investigating plant extracts, their bioactive components, and drug combinations that target iGluRs. Furthermore, gene editing techniques enable the modulation of iGluR activity in specific cell populations, facilitating the development of more precise and personalized therapies targeting iGluRs. In recent years, the neuroprotective effects of steroids have garnered significant attention within the scientific community, highlighting their potential to mitigate neurodegenerative diseases and brain injuries. These findings suggest that steroids, beyond their well-known physiological roles, may offer critical pathways to preserving neural integrity and function. Tayeb et al. performed a systematic review of neuroprotective effects of steroids and ecdysteroids in human neuroblastoma SH-SY5Y cells. Twenty studies included showed activation of antioxidant enzymes and signaling pathways. This finding provides robust evidence for the neuroprotective role of steroids and ecdysteroids in preserving neuronal function in neurodegenerative disorders. The last paper in this issue by Parthasarathy et al. focused on calcium-binding proteins and N-methyl-D-aspartate receptors in stress. Oxidative stress can disrupt calcium homeostasis, leading to the malfunction of calcium-binding proteins, which in turn triggers cellular stress responses and apoptosis. Wistar rats were assigned to two stress inductions, H2O2 or immobilization, for 30 days. The expression of calcium-binding proteins in the hippocampus was shown to be increased by stress, and this was associated with behavioral changes, namely a decrease in mobility and depressive like behavior. Novel therapeutic strategies to protect neurons and other brain cells are currently at various stages of research and development, with some already in clinical trials and others undergoing preclinical assessment.4 Continued progress in understanding the underlying mechanisms of neurodegeneration, along with innovative approaches such as gene editing, targeted molecular treatments, and regenerative medicine, is emerging as potentially beneficial. While challenges remain, advancements in this field demonstrate a constant pursuit of scientific growth and innovation. Persistent research holds promise for developing effective therapies that not only alleviate symptoms but also modify disease progression, providing hope for improved quality of life and outcomes for people suffering from these severe disorders. All authors listed have conceptualized, written and edited the publication, and approved its final version for submission. The authors want to thank Ningning Wang for serving as the managing editor and her highly professional support of all journal operations. Šárka Lehtonen is supported by the Sigrid Juselius Foundation and Jane and Aatos Erkko Foundation. Jukka Jolkkonen is one of Editorial Board members of Neuroprotection. He was blinded from reviewing or making decisions on the manuscript. The remaining author declares no conflict of interest. Not applicable. Not applicable.