CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 15, Issue 10, 2016

Exposure to environmental extremely low-frequency electromagnetic fields (ELF-EMF) in everyday life is increasing and it is a matter of great debate whether exposure to ELF-EMF can be harmful to human health. The neuropathology and symptoms of neurodegenerative disease depends on factors other than genetic predispositions, such as environmental exposure to disease-related risk factors. Research focusing on a possible contribution of ELF-EMF to cell injury and to the development of neurodegenerative disorders is characterized by conflicting data from epidemiological and animal studies. Due to lack of a direct link between neurodegenerative processes and ELF-EMF exposure, our goal was to investigate if ELF-EMF exposure may represent a possible risk factor. In the present study, using neuronal-like SH-SY5Y neuroblastoma cells, we show that the balance between generation and elimination of reactive oxygen species, as well as the balance between pro- and anti-inflammatory cytokines linked to oxidative stress, was maintained ensuring that cells respond properly to ELF-EMF (50Hz /1mT). In SH-SY5Y-exposed cells we observed increased intracellular 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio reflecting the rate of transmitter synthesis, catabolism and release, while matrix metalloproteinases that play critical roles in neuronal cell death were not significantly altered. The results presented here indicate that changes caused by short (1h-3h) and sub-chronic (48 h) exposure to 50Hz/1mT ELF-EMF in SH-SY5Y cells are minor in comparison to the neuronal cell damage expected to underlie neurodegeneration or cognitive impairment. Thus, these results are in accord with epidemiological studies that have provided little support for a link between ELF-EMFs and neurodegeneration.

An increasing number of research evidences indicate linkage between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD); the two most common diseases of aging. In addition, T2DM and AD also share some common pathophysiological features. Therefore, dual therapy that targets both the diseases can be regarded as a beneficial approach. Acetylcholinesterase (AChE) and beta-secretase (BACE) have been considered as potential therapeutic targets for AD. Accordingly, the piece of work presented here describes the binding of anti-diabetic drugs (Jardiance, Suiny and Nesina) with AChE and BACE so as to further investigate connecting bridges concerning the treatment of these two diseases. We have used “Autodock 4.2” for docking experiments. Both, hydrogen bond and hydrophobic interactions were found to be involved in the proper positioning of these diabetic drugs within the catalytic site (CAS) of AChE and BACE enzymes to permit docking. Free energy of binding (ΔG) for 'Jardiance-AChE', 'Suiny-AChE' and 'Nesina-AChE' CAS interactions were found to be –9.21, –7.32 and –10.66 kcal/mol, respectively; while for 'Jardiance-BACE', 'Suiny -BACE' and 'Nesina-BACE' CAS interactions the same were determined to be –8.91, –8.58 and –10.40 kcal/mol, respectively. Hence, these diabetic drugs might act as potent dual inhibitors for the treatment of diabetes-associated neurological disorders. Consequently, the results described herein may form the basis of future dual therapy against the same.

Endoproteolysis is a normal post-translational process in the eukaryotic cell that plays a role in protein evolution allowing protein catabolism and the generation of amino acids. Endoproteolytic cleavage regulates many crucial cellular processes including the activity of many proteins, their protein-protein interactions and the amplification of cell signals. Not surprisingly, disruption or alternation of endoproteolytic cleavage may be the root cause of many human diseases such as Alzheimer’s disease, Huntington’s disease and prion diseases. Most neurodegenerative diseases (ND) are caused by the build-up of misfolded proteins and the promotion of aggregation events. A common event that occurs in these ND is the alteration of endoproteolytic cleavage due to genetic mutations of the associated-proteases or target substrate. Endoproteolytic cleavage resulting in protein truncation has significant effects on the structure and function of a protein representing a common feature of ND. In this review, we will discuss the endoproteolytic cleavage events that lead to ND, namely Alzheimer’s disease, Huntington’s disease and prion diseases.

Neurodegeneration is progressive loss of functional and structural integrity of the central nervous system. Neurodegenerative disorders are yet without any reliable therapy because the neurons of the central nervous system have limited ability to regenerate. Current therapeutic approaches rely mainly on abrogation of symptoms and leave the dying neurons to their fate. Protective and/or rescuing treatments need to be explored fully to suppress neuronal death that will automatically alleviate the symptoms. Adequate precedent exists in literature regarding the neuroprotective activity of endophytes. Endophytes are a class of microorganisms which colonize healthy plant tissues without causing any apparent harm to the host. Chemical moieties from known endophytes have been used against many disease models including neurodegenerative diseases. There is great hope that novel bioactive molecules from newer endophytes can impede pathogenic mechanisms and progression of many diseases. In this review, we will discuss promising pharmacological or clinical relevance of endophytes against various neurodegenerative diseases.

Parkinson's disease (PD) is a devastating and progressive movement disorder characterized by symptoms of muscles rigidity, tremor, postural instability and slow physical movements. Biochemically, PD is characterized by lack of dopamine production and its action due to loss of dopaminergic neurons and neuropathologically by the presence of intracytoplasmic inclusions known as Lewy bodies, which mainly consist of presynaptic neuronal protein, α-synuclein (α-syn). It is believed that alteration in α-syn homeostasis leads to increased accumulation and aggregation of α-syn in Lewy body. Based on the important role of α-syn from pathogenesis to therapeutics, the recent researches are mainly focused on deciphering the critical role of α-syn at advanced level. Being a major protein in Lewy body that has a key role in pathogenesis of PD, several model systems including immortalized cell lines (SH-SY5Y), primary neuronal cultures, yeast (saccharomyces cerevisiae), drosophila (fruit flies), nematodes (Caenorhabditis elegans) and rodents are being employed to understand the PD pathogenesis and treatment. In order to study the etiopathogensis and develop novel therapeutic target for α -syn aggregation, majority of investigators rely on toxin (rotenone, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine, 6-hydroxydopamine, paraquat)-induced animal models of PD as a tool for basic research. Whereas, cell and tissue based models are mostly utilized to elucidate the mechanistic and molecular pathways underlying the α -syn induced toxicity and therapeutic approaches in PD. Gene modified mouse models based on α-syn expression are fascinating for modeling familial PD and toxin induced models provide a suitable approach for sporadic PD. The purpose of this review is to provide a summary and a critical review of the involvement of α-syn in various in vitro and in vivo models of PD based on use of neurotoxins as well as genetic modifications.

Neurological manifestations or disorders associated with the central nervous system are among the most common and important clinical characteristics of antiphospholipid syndrome (APS). Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse ‘non-criteria’ neurological disorders or manifestations (i.e., headache, migraine, bipolar disorder, transverse myelitis, dementia, chorea, epileptic seizures, multiple sclerosis, psychosis, cognitive impairment, Tourette’s syndrome, parkinsonism, dystonia, transient global amnesia, obsessive compulsive disorder and leukoencephalopathy) have been observed in APS patients. To date, the underlying mechanisms responsible for these abnormal neurological manifestations in APS remain unclear. In vivo experiments and human observational studies indicate the involvement of thrombotic events and/or high titers of antiphospholipid antibodies in the neuro-pathogenic cascade of APS. Although different types of neurologic manifestations in APS patients have successfully been treated with therapies involving anti-thrombotic regimens (i.e., anticoagulants and/or platelet antiaggregants), antineuralgic drugs (i.e., antidepressants, antipsychotics and antiepileptics) and immunosuppressive drugs alone or in combination, evidence-based guidelines for the management of the neurologic manifestations of APS remain unavailable. Therefore, further experimental, clinical and retrospective studies with larger patient cohorts are warranted to elucidate the pathogenic linkage between APS and the central nervous system in addition to randomized controlled trials to facilitate the discovery of appropriate medications for the ‘non-criteria’ neurologic manifestations of APS.

Injuries to the spinal cord often have devastating physiological impacts due to the organ’s vital role in neuro-impulse communications between muscles and the brain. Spinal Cord Injuries (SCIs) have recently been estimated to affect up to 80,000 individuals per year worldwide, with most occurring following a traumatic event. Unfortunately, effective treatments standardised globally for patients with SCIs have not yet been established. For many years, inadequate understanding of the complexities of the Central and Peripheral Nervous Systems and Neurogenesis has limited progression towards effective cures. However, in the last century, scientific advancements have generated new paradigms for medical treatments of SCIs. Basic as well as translational studies have progressed to such an extent that many kinds of protective and regenerative therapeutics are available in clinical trials. In particular, uncovering the mechanisms responsible for controlling the pluripotent state of Human Embryonic Stem Cells (hESCs) was proved vital for recognizing the prospective role in regenerative medicine for SCIs. Elucidating knowledge of neurogenesis alongside hESCs in relation to SCIs has been crucial for critical assessments of the existing translational therapeutic strategies for SCIs.

AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. eta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

Background: Major Depressive disorder (MDD) is often accompanied by cognitive deficits, involving attention, learning, memory and executive functioning. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) show efficacy on affective symptoms, but it is unclear whether or not they improve cognitive symptoms. Methods: We carried out a 12 week-prospective observational study in two cohorts of recurrent moderate-severe partial responder MDD patients, to test the hypothesis that SSRIs and/or SNRIs may affect cognitive symptoms and assess whether or not such an effect was correlated to their effect on affective symptoms. All patients underwent cognitive and neuropsychiatric assessment at baseline, 4- and 12-week follow-up. Thirty-three patients in the SSRI- and sixteen patients in the SNRI-cohort completed the follow-up. Results: Both SSRIs and SNRIs reduced affective symptoms and improved global cognitive function. Both SSRIs and SNRIs improved executive function and verbal memory. Global cognitive function, verbal memory and executive function improved both in full and partial responder patients. Finally, there was no correlation between baseline Mini Mental State Examination, Montreal Cognitive Assessment and Frontal Assessment Battery scores and the mean change in Hamilton Psychiatric Rating scale for Depression or Beck Depression Inventory at the end of the 12 weeks of treatment. Conclusion: Present data show that SSRIs and SNRIs improve cognitive symptoms in MDD independently from their efficacy on affective symptoms. Affective and cognitive symptoms may represent distinct psychopathological dimensions of MDD with different response to antidepressant drugs.

KCa3.1 protein is part of a heterotetrameric voltage-independent potassium channel, the activity of which depends on the intracellular calcium binding to calmodulin. KCa3.1 is immensely significant in regulating immune responses and primarily expressed in cells of hematopoietic lineage. It is one of the attractive pharmacological targets that are known to inhibit neuroinflammation. KCa3.1 blockers mediate neuroprotection through multiple mechanisms, such as by targeting microglia-mediated neuronal killing. KCa3.1 modulators may provide alternative treatment options for neurological disorders like ischemic stroke, Alzheimer disease, glioblastoma multiforme, multiple sclerosis and spinal cord injury. This review is an attempt to draw attention towards KCa3.1 channel, which was never exploited to its full potential as a viable therapeutic candidate against various neurological disorders.

Despite the numerous challenges associated with the application of nanotechnology in neuroscience, it promises to have a significant impact on our understanding of how the nervous system works, how it fails in disease, and the development of earlier and less-invasive diagnostic procedures so we can intervene in the pre-clinical stage of neurological disease before extensive neurological damage has taken place. Ultimately, both the challenges and opportunities that nanotechnology presents stem from the fact that this technology provides a way to interact with neural cells at the molecular level. In this review we provide a neurobiological overview of key neurological disorders, describe the different types of nanomaterials in use and discuss their current and potential uses in neuroscience. We also discuss the issue of toxicity in these nanomaterials. This review presents many of the different applications that advances in nanotechnology are having in the field of neurological sciences, especially the high impact they are having in the development of new treatment modalities for neurological disorders that will induce the expected physiological response while minimizing undesirable secondary effects. In conclusion, we weigh in on what the promises and challenges are for future development in this groundbreaking field.

Background: Dopamine agonists are utilized clinically as an initial treatment in younger Parkinson’s disease patients to delay the side effects associated with commencement of levodopa medication. These agonists also serveas adjunctive therapeutics with levodopa to lower the incidence of adverse motor symptoms in advanced stages of the disease. Objectives: To compare the neuroprotective effects of the dopamine agonists pergolide and pramipexole on ferrous sulfate-induced neurotoxicity in dopaminergic neurons from primary mesencephalic cell culture. Methods: Pergolide (0.001-1 μM) and pramipexole (0.01-200 μM) were administered to 8 day primary murine mesencephalic cultures for 24 h. in the presence or absence of desferal, sulpiride or cycloheximide. Ferrous sulfate (450 μM) was then added for 24 hrs. Lactate dehydrogenase was assayed in the supernatant, glutathione concentrations measured in cell lysates and fixed cells were stained for tyrosine hydroxylase. Results: Ferrous sulphate induced neurotoxity in cultures (p<0.0001) was abolished in the presence of the iron chelator desferal (p<0.008). Both pergolide (p<0.0001) and pramipexole (p<0.0001) significantly protected dopaminergic neurons against ferrous sulfate induced neurotoxicity and pramipexole helped preserve neurite morphology. Pramipexole treatment significantly reduced lactate dehydrogenase release (p<0.0001) as a measure of cellular injury. The dopamine receptor antagonist sulpiride (p<0.0001) and the protein synthesis inhibitor cycloheximide (p<0.0001) reduced the neuroprotective effects of pergolide indicating the involvement receptor stimulation and de novo protein synthesis in pergolide-mediated neuroprotection. Pramipexole also significantly reversed the decrease in cellular glutathione concentrations induced by ferrous sulfate (p<0.001). Conclusion: Both pergolide and pramipexole protect dopaminergic neurons against the neurotoxicity of ferrous sulfate. Pergolide specifically protects dopaminergic neurons through activation of dopamine receptors and de novo protein synthesis whereas pramipexole shows an overall effect through an antioxidant mechanism.

A series of new 8-alkylamino-5, 6-dihydro-4H-benzo[f][1,2,4]triazolo [4,3-a]azepine derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test. The results of these tests showed that 8-heptylamino-5,6- dihydro-4H-benzo[f][1,2,4] triazolo[4,3-a]azepine (7g) was the most promising compound, with median effective dose (ED50) of 19.0 mg/kg, and protective index (PI) value of 14.8 in the MES test, which is much higher than the PI value of the prototype antiepileptic drug carbamazepine (PI = 8.1), phenytoin (PI = 6.9), phenobarbital (PI = 3.2), and sodium valproate (PI = 1.6). The possible structure–activity relationship was discussed.