CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 19, Issue 3, 2020

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords “insulin”; “insulin resistance”; “Alzheimer’s disease”; “Parkinson’s disease” in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) is a rational target in Alzheimer’s Disease (AD) drug development due to its role in amyloidogenic cleavage of Amyloid Precursor Protein (APP) in generating Amyloid β (Aβ). This β-secretase cleaves not only Amyloid Precursor Protein (APP) and its homologues, but also small series of substrates including neuregulin and β subunit of voltage-gated sodium channel that play a very important role in the development and normal function of the brain. Moreover, BACE1 is modulated at the post-translational level by several factors that are associated with both physiological and pathological functions. Since the discovery of BACE1 over a decade ago, medicinal chemistry and pharmacokinetics of BACE1 small molecule inhibitors have proven challenging for the treatment of Alzheimer’s disease.

Parkinson’s Disease (PD) is a neurodegenerative disease involving degeneration of dopaminergic neurons of the nigrostriatal pathways. Over the past decades, most of the medications for the treatment of PD patients have been used to modulate dopamine concentrations in the basal ganglia. This includes levodopa and its inhibitory metabolizing enzymes. In addition to modulating dopamine concentrations in the brain, there are D2-like dopamine receptor agonists that mimic the action of dopamine to compensate for the deficit in dopamine found in PD patients. Muscarinic antagonists’ drugs are used rarely due to some side effects. Monoamine oxidase inhibitors are among the first in line, and are considered popular drugs that reduce the metabolism of dopamine in PD patients. Furthermore, we discussed in this review the existence of certain glutamate receptor antagonists for the treatment of PD. Alternatively, we further discussed the potential therapeutic role of adenosine (2A) receptor antagonists, such as tozadenant and istradefylline in the treatment of PD. We also discussed the important role of serotonin1A receptor agonist, adrenergic autoreceptors (α2) antagonists and calcium channel blockers in the treatment of PD. Finally, neurotrophic factors, such as glial cell line-derived neurotrophic growth factor and brain-derived neurotrophic factor are considered the primary factors for neuroprotection in PD.

The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway has a main role against oxidative stress and inflammation. Spinal Cord Injury (SCI) leads to the high secretion of inflammatory cytokines and reactive oxygen species, which disturbs nervous system function and regeneration. Several studies have indicated that the activation of the Nrf2 signaling pathway may be effective against inflammation after SCI. The experimental studies have indicated that many chemical and natural agents act as Nrf2 inducer, which inhibits the SCI progression. Thus, the finding of novel Nrf2- inducer anti-inflammatory agents may be a valuable approach in drug discovery. In the present review, we discussed the Nrf2 signal pathway and crosstalk with the NF-ΚB pathway and also the impact of this pathway on inflammation in animal models of SCI. Furthermore, we discussed the regulation of Nrf2 by several phytochemicals and drugs, as well as their effects on the SCI inhibition. Therefore, the current study presented a new hypothesis of the development of anti-inflammatory agents that mediate the Nrf2 signaling pathway for treating the SCI outcomes.

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain stimulation technique that is being actively explored as a potential therapeutic modality in various neuropsychiatric disorders, such as depression, neuropathic pain, epilepsy, multiple sclerosis, and neurodegenerative disorders, including the Parkinson’s and Alzheimer’s disease. The Food and Drug Administration (FDA) approved rTMS for the treatment of major depression, migraine-associated headaches, and Obsessive Compulsive Disorder (OCD). The fact that a significant proportion of patients suffering from these disorders fail to respond to current pharmacological interventions indicates the need for alternative therapies like rTMS. Objective: The objective was to find and summarize all studies combining the use of rTMS and pharmacological interference in vitro, in order to facilitate future studies. Methods: The results of studies combining the use of rTMS with pharmacological interference in vitro were focused on. The PubMed database was searched using the terms “rTMS”, “repetitive”, “transcranial”, “magnetic”, “stimulation”, “in vitro”, “in vivo”, “cell cultures” untilMarch 2019 and 7 eligible studies were found. Results: Overall results show a synergistic effect of rTMS and pharmacotherapy in vitro with additive effectiveness, better prognosis, and superior potential management. Conclusion: The limited amount of knowledge denotes the need for additional in vitro studies on the combination of rTMS and pharmacotherapy, which could be extended to in vivo studies and ultimately help design clinical trials so as to improve the therapeutic management of patients with a wide array of neuropsychiatric disorders.

Aim: The aim of this study is to examine the effect of etifoxine on β-amyloid-induced toxicity models. Background: Etifoxine is an anxiolytic compound with a dual mechanism of action; it is a positive allosteric modulator of GABAergic receptors as well as a ligand for the 18 kDa mitochondrial Translocator Protein (TSPO). TSPO has recently raised interest in Alzheimer’s Disease (AD), and experimental studies have shown that some TSPO ligands could induce neuroprotective effects in animal models. Objective: In this study, we examined the potential protective effect of etifoxine in an in vitro and an in vivo model of amyloid beta (Aβ)-induced toxicity in its oligomeric form, which is a crucial factor in AD pathologic mechanisms. Methods: Neuronal cultures were intoxicated with Aβ1-42, and the effects of etifoxine on oxidative stress, Tau-hyperphosphorylation and synaptic loss were quantified. In a mice model, behavioral deficits induced by intracerebroventricular administration of Aβ25-35 were measured in a spatial memory test, the spontaneous alternation and in a contextual memory test, the passive avoidance test. Results: In neuronal cultures intoxicated with Aβ1-42, etifoxine dose-dependently decreased oxidative stress (methionine sulfoxide positive neurons), tau-hyperphosphorylation and synaptic loss (ratio PSD95/synaptophysin). In a mice model, memory impairments were fully alleviated by etifoxine administered at anxiolytic doses (12.5-50mg/kg). In addition, markers of oxidative stress and apoptosis were decreased in the hippocampus of these animals. Conclusion: Our results have shown that in these two models, etifoxine could fully prevent neurotoxicity and pathological changes induced by Aβ. These results confirm that TSPO ligands could offer an interesting therapeutic approach to Alzheimer’s disease.