Neurological disorders represent major health concerns in terms of comorbidity and mortality worldwide. Despite a tremendous increase in our understanding of the pathophysiological processes involved in disease progression and prevention, the accumulated knowledge so far resulted in relatively moderate translational benefits in terms of therapeutic interventions and enhanced clinical outcomes. Aiming at specific neural molecular pathways, different strategies have been geared to target the development and progression of such disorders. The kallikrein-kinin system (KKS) is among the most delineated candidate systems due to its ubiquitous roles mediating several of the pathophysiological features of these neurological disorders as well as being implicated in regulating various brain functions. Several experimental KKS models revealed that the inhibition or stimulation of the two receptors of the KKS system (B1R and B2R) can exhibit neuroprotective and/or adverse pathological outcomes. This updated review provides background details of the KKS components and their functions in different neurological disorders including temporal lobe epilepsy, traumatic brain injury, stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis and glioma. Finally, this work will highlight the putative roles of the KKS components as potential neurotherapeutic targets and provide future perspectives on the possibility of translating these findings into potential clinical biomarkers in neurological disease.

Background: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence.Methods: Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines.Results: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment.Conclusion: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence.

Nervous system tumors represent some of the highly aggressive cancers in both children and adults, particularly neuroblastoma and glioblastoma. Many studies focused on the pathogenic role of the Akt pathway and the mechanistic target of Rapamycin (mTOR) complex in mediating the progression of various types of cancer, which designates the Akt/mTOR signaling pathway as a master regulator for cancer. Current studies are also elucidating the mechanisms of cancer stem cells (CSCs) in replenishing tumors and explicating the strong correlation between the Akt/mTOR pathway and CSC biology. This instigates the development of novel treatments that target CSCs via inhibiting this pathway to prevent recurrence in various cancer subtypes. In accordance, neuroblastoma and glioblastoma tumors are believed to originate from stem/progenitor cells or dedifferentiated mature neural/glial cells transformed into CSCs, which warrants targeting this subpopulation of CSCs in these tumors. In our study, Triciribine and Rapamycin were used to assess the role of inhibiting two different points of the Akt/mTOR pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) human cell lines and their CSCs. We showed that both drugs minimally decrease the survival of U251 and SH-SY5Y cells in a 2D model, while this effect was much more pronounced in a 3D culture model. Triciribine and Rapamycin decreased migratory abilities of both cell lines and decreased their sphere-forming units (SFU) by extinguishing their CSC populations. Together, we concluded that Rapamycin and Triciribine proved to be effective in the in vitro treatment of glioblastoma and neuroblastoma, by targeting their CSC population.

Although neuropsychiatric (NP) disorders are among the top causes of disability worldwide with enormous financial costs, they can still be viewed as part of the most complex disorders that are of unknown etiology and incomprehensible pathophysiology. The complexity of NP disorders arises from their etiologic heterogeneity and the concurrent influence of environmental and genetic factors. In addition, the absence of rigid boundaries between the normal and diseased state, the remarkable overlap of symptoms among conditions, the high inter-individual and inter-population variations, and the absence of discriminative molecular and/or imaging biomarkers for these diseases makes difficult an accurate diagnosis. Along with the complexity of NP disorders, the practice of psychiatry suffers from a “top-down” method that relied on symptom checklists. Although checklist diagnoses cost less in terms of time and money, they are less accurate than a comprehensive assessment. Thus, reliable and objective diagnostic tools such as biomarkers are needed that can detect and discriminate among NP disorders. The real promise in understanding the pathophysiology of NP disorders lies in bringing back psychiatry to its biological basis in a systemic approach which is needed given the NP disorders’ complexity to understand their normal functioning and response to perturbation. This approach is implemented in the systems biology discipline that enables the discovery of disease-specific NP biomarkers for diagnosis and therapeutics. Systems biology involves the use of sophisticated computer software “omics”-based discovery tools and advanced performance computational techniques in order to understand the behavior of biological systems and identify diagnostic and prognostic biomarkers specific for NP disorders together with new targets of therapeutics. In this review, we try to shed light on the need of systems biology, bioinformatics, and biomarkers in neuropsychiatry, and illustrate how the knowledge gained through these methodologies can be translated into clinical use providing clinicians with improved ability to diagnose, manage, and treat NP patients.

Stroke is the second leading cause of death worldwide and a major cause of long-term severe disability representing a global health burden and one of the highly researched medical conditions. Nanostructured material synthesis and engineering have been recently developed and have been largely integrated into many fields including medicine. Recent studies have shown that nanoparticles might be a valuable tool in stroke. Different types, shapes, and sizes of nanoparticles have been used for molecular/biomarker profiling and imaging to help in early diagnosis and prevention of stroke and for drug/RNA delivery for improved treatment and neuroprotection. However, these promising applications have limitations, including cytotoxicity, which hindered their adoption into clinical use. Future research is warranted to fully develop and effectively and safely translate nanoparticles for stroke diagnosis and treatment into the clinic. This work will discuss the emerging role of nanotheragnostics in stroke diagnosis and treatment applications.