CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 19, Issue 8, 2020

The concepts of the neurobiology of nerve injury, fibrosis and regeneration are critical. Millions of people worldwide are affected every year by traumatic and non-traumatic forms of injury to the spinal cord or the peripheral nerves that cause huge socioeconomic burdens. Innumerable studies over the last few decades have studied the disease pathogenesis. Also, several strategies and techniques have undertaken to repair injuries in the PNS and CNS, but all have resulted in suboptimal functional outcomes. In this review, we have provided a general description of injury-induced scarring and fibrosis in the PNS and CNS. We also discuss the important signaling factors and mechanistic pathways that regulate the disease pathogenesis. We further discuss the current paradigms that suggest the involvement of essential factors in and during disease progression. We believe that readers and researchers will gain key insights into how fibrosis regulates the regenerative process in the PNS and CNS. We hope this review will help clinicians and scientists to address an unmet medical need and direct further studies towards the identification of better therapeutic approaches.

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

Autoimmune Encephalitides (AE) comprises a group of diseases with antibodies against neuronal synaptic and cell surface antigens. Since the discovery of the most common subtype, NMethyl- D-Aspartate (NMDA) receptor encephalitis, an astonishing number of novel disease-causing antibodies have been described. This includes other glutamatergic and GABAergic receptor antibodies and antibodies against various other surface proteins. Many of these novel conditions present as limbic encephalitis with memory impairment, psychiatric features and epileptic seizures, often alongside subtype specific clinical features. Others present with a clinical disease course specific to the antibody. In contrast to the well-known paraneoplastic syndromes with antibodies directed against intracellular antigens (e.g. limbic encephalitis with Hu antibodies), autoimmune encephalitides are often highly responsive to immunotherapy, with a good outcome if diagnosed and treated early. Prognosis depends on aggressive immunotherapy, often with a combination of corticosteroids, intravenous immunoglobulin, plasma exchange or in some cases anti-CD20 therapy and cyclophosphamide. Other treatment regimens exist, and prognosis varies between disease subtypes and occurrence of underlying cancer. We review current knowledge on subtype-specific clinical presentation, disease mechanisms, diagnosis including pitfalls, treatment paradigms and outcome in autoimmune encephalitides, and provide suggestions for future research.

The unmet need for a safe treatment that significantly improves the overall survival, as well as the quality of life of patients with brain tumors, has urged researchers to work out new treatment modalities. About 15 years ago, it was shown that alternating electric fields significantly impair the growth of cancer cells. Recently, this potentially revolutionary approach called Tumor Treating Fields (TTFs) has been FDA-approved for the treatment of glioblastoma as well as mesothelioma. However, despite the promising reports on the potential of TTFs, the precise knowledge of the mechanisms of action is still lacking. The purpose of this review is, thus, to present the current state of research and to highlight the variety of ultrastructural effects of TTFs. Moreover, the aim is to bring to the foreground less discussed mechanisms of action of TTFs, which might develop into novel therapeutic approaches. Therefore, a systematic literature search in Ovid Medline and Embase was performed on clinical and preclinical data concerning TTFs. The alternating electric fields force cellular components to aberrant dynamics, among which the most evident is the inhibition of the mitotic spindle assembly leading to impaired cancer cell division and cell death. However, a variety of other microstructural events induced by TTFs, such as inhibition of DNA repair and cell migration, as well as an enhancement of anti- tumor immune response and membrane permeability, have been reported. In addition, apart from a suggested interference with angiogenesis, no TTF-induced effects on normal cells have been described so far.

Impulse Control Disorders (ICDs) and related disorders are common side effects of dopaminergic treatment in Parkinson’s Disease (PD) and are associated with negative effects on mental and physical health, quality of life and interpersonal relationships. Current management options are limited, as a reduction of dopaminergic medication often leads to worsening of motor symptoms or dopamine agonist withdrawal syndrome. The aim of this review was to investigate if ICDs improve, worsen, or remain stable after Subthalamic Nucleus Deep Brain Stimulation (STN-DBS). We reviewed retrospective, prospective and randomized-controlled studies published between 2000 and 2019 examining the effect of STN-DBS on one or more ICDs. The number of participants, time of follow-up, methods used to measure ICDs, type of ICDs, the incidence of ICDs before STN-DBS, the incidence of improvement (remission or reduction) of ICDs after STN-DBS, the incidence of de novo ICDs after STN-DBS, stimulation parameters, lead position, change in motor score and change in medication are reported for each study. Available studies suggest that ICDs improve after STN-DBS in most patients and that persisting new-onset ICDs induced by STN-DBS are rare. However, more randomized-controlled studies are needed to confirm the findings and to further investigate the underlying mechanisms.

Background: The human neuroblastoma cell line, SH-SY5Y, has been widely used in neuroscience research, especially in studies related to Parkinson's disease. However, differences between clones have been demonstrated, highlighting the importance to characterize the properties of this cell line carefully. Objective: The aim of this study was to characterize the phenotype of undifferentiated and differentiated SH-SY5Y cells using various differentiation protocols. Methods: A morphological and quantitative analysis of markers related to dopaminergic and cholinergic neurons, but also other phenotypes, was performed. Results: Differentiated cells showed the typical neuronal morphology. Undifferentiated cells expressed low levels of Tyrosine Hydroxylase (TH) and higher levels of the high-affinity Choline Transporter (CHT1). Staurosporine (ST)-differentiation resulted in the highest number of THimmunoreactive cells, followed by phorbol ester Phorbol-12-Myristate-13-Acetate (PMA), whereas differentiation with Brain-Derived Neurotrophic Factor (BDNF) did not increase TH-immunoreactive cells. TH, dopamine β-hydroxylase and vesicular monoamine transporter-2 were also significantly upregulated in ST-differentiated cells compared to both undifferentiated and Retinoic Acid (RA)- differentiated cells. RA induced the highest number of CHT1-immunoreactive cells while ST- and BDNF-differentiation reduced CHT1-immunoreactive cells, indicating a decrease in the cholinergic phenotype. The presynaptic neuronal protein, α-synuclein, was significantly upregulated in RA- and ST-treated cells compared to undifferentiated cells. Ascorbic acid increased the number of CHT1-immunoreactive cells in all differentiation procedures and ST-differentiated TH-positive cells significantly. Conclusion: Our findings indicate that a quantitative characterization of the phenotype is crucial when using SH-SY5Y cells to study the pathogenesis or evaluate compounds for treatment of neurodegenerative diseases.

Background: Currently approved Alzheimer’s disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. Objective: To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. Methods: The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. Results: All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 μM) and 12a (IC50= 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. Conclusion: These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer's disease agents.