CNS & Neurological Disorders - Drug Targets - Volume 14, Issue 7, 2015

The aim of the present study was to analyze if the genetic polymorphisms might predict suicide attempts in mental disorder patients. The literature review and meta-analysis were conducted using the PubMed/Medline, Web of science and Scopus database using the terms: “5-HTT or SLC6A4 or 5-SERT and suicide, suicidal ideation or suicidal behavior or suicidal attempt”. Thirty articles were analyzed. We found 17 articles that showed association and 13 articles that showed no association between LPR serotonin transporter polymorphism and suicide. A higher study of suicide identified the serotonin transporter polymorphism in patients with schizophrenia, mental disorder, major depression and bipolar disorder. There is an association between the serotonin-transporter-linked polymorphic region and suicidal behavior. The mental disorders with greater relationship with the suicide were the bipolar disorder, major depression and schizophrenia. The L allele had higher risk for suicide.

Aβ-induced astrogliosis can worsen the eziopathogenesis of Alzheimer disease (AD) by the release of proinflammatory and pro-oxidant mediators. Activated glial cells may release also pro-angiogenic molecules. The role of angiogenesis in AD is still controversial: although angiogenesis brings oxygen and nutrients to injured tissue, it may also exacerbate reactive gliosis. Moreover, by altering blood-brain barrier permeability pro-angiogenic mediators promote passage of inflammatory/immune-competent cells into the brain, thereby exacerbating gliosis. The release of proangiogenic factors during astrogliosis may thus be a key-step in controlling AD progression. The endogenous fatty acid amide, palmitoylethanolamide (PEA), is a pleiotropic mediator exerting anti-inflammatory, antinociceptive and antiangiogenic effects in several in vitro and in vivo models of chronic-degenerative disease. In this study, we investigated the effects of PEA in AD angiogenesis and neuroinflammation by using conditioned medium from untreated and Aβ-treated C6 rat astroglioma cells and HUVEC human endothelial cells. PEA (10-8-10-6 M) concentration-dependently reduced expression of pro-inflammatory and pro-angiogenic markers in Aβ (1 μg/mL)-stimulated C6 cells. Moreover, culture medium from PEA-treated C6 cells reduced HUVEC cell proliferation as compared to cells treated with conditioned medium from Aβ-treated C6 cells. Immunocytochemical analysis revealed that PEA treatment inhibited nuclear levels of mitogen-activated protein kinase 1 (the main pro-angiogenic pathway) and cytoplasmic vascular endothelial growth factor in HUVEC cells receiving C6 conditioned medium. Finally, the peroxisome proliferator-activated receptor alpha inhibitor GW6471, added to Aβ-treated C6 cells blocked all PEA effects in this model, suggesting that PEA acts through a proliferator-activated receptor alpha-dependent mechanism on astroglial cells. Collectively, these data support the potential therapeutic utility of PEA in AD.

In this review we discuss that peripheral and central activation of the Toll-like receptor 2/4 (TLR2/4) Radical Cycle may underpin the pathophysiology of immune-related chronic fatigue secondary to other medical diseases and conditions. The TLR Radical Cycle plays a role in illnesses and conditions that are disproportionately commonly comorbid with secondary chronic fatigue, including a) neuroinflammatory disorders, e.g. Parkinson’s disease, stroke, depression, psychological stressors, and b) systemic disorders, e.g. (auto)immune disorders, chronic obstructive pulmonary disease, ankylosing spondylitis, chronic kidney disease, inflammatory bowel disease, cardiovascular disease, incl. myocardial infarction, cancer and its treatments. Increased TLR signaling is driven by activated immuneinflammatory and oxidative and nitrosative stress pathways, pathogen derived molecular patterns, including lipopolysaccharides, and damage associated molecular patterns (DAMPs). Newly formed redox-derived DAMPs, secondary to oxidative processes, may further activate the TLR complex leading to an auto-amplifying TLR Radical feedback loop. Increased gut permeability with translocation of gram negative bacteria and LPS, which activates the TLR Radical Cycle, is another pathway that may play a role in most of the abovementioned diseases and the secondary fatigue accompanying them. It is concluded that secondary fatigue may be associated with activation of the TLR Radical Cycle pathway due to activated immune-inflammatory pathways, classical and redox-derived DAMPs and PAMPs plays a role in its pathophysiology. Such an activation of the TLR Radical Cycle pathway may also explain why the abovementioned conditions are primed for an increased expression of secondary chronic fatigue. Targeting the TLR Radical Cycle pathway may be an effective method to treat TLR-Radical Cycle-related diseases such as secondary chronic fatigue.

The aim of the study was to determine anticonvulsant activity of lamotrigine (LTG) after acute and chronic treatment in four different protocols against maximal electroshock-induced seizures in mice. Such a knowledge seems to be valuable in view of the fact that all interactions between LTG and other drugs are evaluated in acute, not chronic, experiments. Electroconvulsions were produced by means of alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were assessed in the chimney test and in passive avoidance task, respectively. Brain and plasma concentrations of LTG were measured by HPLC. Chronic treatment with LTG (2 injections for 14 days) significantly potentiated the anticonvulsant effects of this antiepileptic in the maximal electroshock test in mice, significantly decreasing ED50 value for this antiepileptic. No impairment in motor coordination or long-term memory after acute or chronic treatment with LTG was noted. Nevertheless, prolonged treatment aggravated toxicity of LTG assessed in the chimney test as TD50 value. Repeated administration of LTG significantly increased plasma and brain concentrations of the antiepileptic drug when compared to the control group (single drug application). In conclusion, anticonvulsant action of LTG in the maximal electroshock test in mice may change, depending on the length of therapy. Both acute and chronic protocols are necessary in preclinical assessment of the anticonvulsant effects of drugs and possible interactions between them.

Researchers have been using the electroencephalogram to better understand the cognitive and neurobiological bases of panic disorder (PD) through the P300 component; this is an electric potential of the cerebral cortex that is generated in response to external sensorial stimuli and which involves more complex neurophysiological processes related to stimulus interpretation; it is then used to investigate possible alterations in the information processing and attention of patients suffering from this disorder. Aiming to verify the results found by experimental articles already published about P300 in PD patients and the information processing differences between PD patients and healthy controls, a systematic review of the PubMed and Institute for Scientific Information databases was conducted. The selection criterion involved those articles, written in English, which referred to an experimental research that focused on the P300 component, with a sample composed of PD (or panic attacks) patients. Seven articles were found that fit the selected criteria. Most of the articles show that these patients suffer from: impaired information processing and attention, an inability to automatically respond to new stimuli, and impaired interpretation of internal and external stimuli related to the disorder. Such impairment may be related to an unspecified dysfunction in the limbic-reticular structures, which would affect: active, focused and short-term attention, working and short-term memory, recognition and decision making. Some limitations were highlighted, such as the use of small samples and possible comorbidity with other disorders, which did not allow clearer results. This research can contribute to understand the neurobiological differences of PD patients and develop treatments based on such evidence.

Astrocytes, the star shaped glial cells, are known to possess supportive and homeostatic role for the neurons. Recently, reactive gliosis, which involves alterations in functioning and phenotype of different glial cells, has been implicated in Alzheimer's Disease (AD). Studies have revealed that astrocyte response to gross tissue damaging injury leads to anisomorphic astrogliosis reinforcing a cascade of events, eventually increasing the pathogenesis of AD and many other neurodegenerative disorders. This review presents the involvement of reactive astrocytes in reduced Aβ clearance and in neuro-neglect hypothesis. Understanding of reactivity and fundamental biology of astrocytes may open new avenues of alternative treatments and therapeutic strategies targeting astrocytes and related events for the treatment of AD.

Crocus sativus L. (Iridaceae) is an important member of the genus Crocus having high medicinal value. Its dried stigmas, known as “saffron” are being widely used form past many centuries as a food additive, coloring agent, flavoring agent and a potential source of traditional medicine. The stigmas along with other botanical parts of Crocus sativus are being extensively used in ethnomedical treatment of varied central nervous system diseases. In line with its ethnomedical importance, several preclinical studies have been carried out to validate its traditional uses, identify active principle(s), understand pharmacological basis of therapeutic action and explore novel medicinal uses. The bioactive components of Crocus sativus have been found to modulate several synaptic processes via direct/indirect interplay with neurotransmitter receptor functions, interaction with neuronal death/survival pathways and alteration in neuronal proteins expression. Many clinical studies proving beneficial effect of Crocus sativus in depressive disorders, Alzheimer's disease and some other neurological abnormalities have also been carried out. Based on the vast literature reports available, an attempt has been made to comprehend the fragmented information on neuropharmacological aspects, chemistry and safety of Crocus sativus. Although the plant has been well explored, but still a large scope of future preclinical and clinical research exist to explore its potential in neurological diseases, that has been discussed in depth in the present review.

Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and tipically affecting a variety of bodily systems including the immune system. Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system. Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients. Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.

The primary pathology of the human central nervous system disease multiple sclerosis (MS) and the animal counterpart experimental autoimmune encephalomyelitis (EAE) includes immunological and inflammatory events. Immune system involvement in MS has been widely debated but the role of inflammation has received less attention. Classic acute inflammation features vasculitis, resident tissue macrophage and mast cell participation plus the involvement of circulatory-derived neutrophils and platelets. Pre-lesion development in MS incorporates cerebral vasculitis, activated resident microglia in normal appearing white matter together with infiltrating cell types and factors indicative of an acute inflammatory reaction. Similarly, the formation of perivascular lesions during early EAE includes characteristic neurovasculitis, the participation of central nervous system microglial phenotypes plus haemopoietic cells and mediators, signifying an ongoing acute inflammatory response. EAE has been extensively used as a screen to select drugs for MS treatment but has been criticised as unrepresentative of the human condition due to fundamental differences in disease induction and pathogenesis. The review provides compelling evidence for a distinct acute inflammatory phase in MS lesion formation that is convincingly reproduced in early EAE pathology. Moreover, consideration of drug efficacy studies undertaken during initial EAE validates the occurrence of an acute inflammatory phase in disease pathogenesis. Critical appraisal, recognition and acceptance of the mutual acute inflammatory components inherent in the primary pathology of MS and EAE reveals new targets and encourages confident and reliable employment of the animal model in the assessment of novel compounds for the control of key primary pathological events in human demyelinating disease.

Telomeric repeat containing RNAs (TERRA) are small RNA molecules synthesized from telomeric regions which were previously considered as silent genomic domains. In normal cells, these RNAs are transcribed in a direction from subtelomeric region towards the chromosome ends, but in case of cancer cells, their expression remains limited or absent. Telomerase is a rate limiting enzyme for cellular senescence, cancer and aging. Most of the studies deal with the manipulation of telomerase enzyme in cancer and aging either by synthetic oligonucleotide or by natural phytochemicals. Here, we collected evidences and discussed intensely about the bio-molecular structure of TERRA, naturally occurring ligands of telomerase, and their genetic and epigenetic regulations in aging associated diseases. Due to their capability to act as naturally occurring ligands of telomerase, these RNAs can overcome the limitations possessed by synthetic oligonucleotides, which are aimed against telomerase. Drugs specifically targeting TERRA molecules could modulate telomerase-mediated telomere lengthening. Thus, targeting TERRA-mediated regulation of telomerase would be a promising therapeutic strategy against cancer and age-associated diseases.

Lewy bodies (LBs) are characteristic hallmarks of Parkinson’s disease (PD). However, their role in the pathology of PD is not established yet. Are they primary events in the neurodegenerative process or only secondary phenomena? Are they signs of protecting neurons from toxicity or are they toxic per se? How are they are formed? Are LBs targets for therapeutic strategies? Addressing these questions may be of pivotal importance to unravel the basic mechanisms of neurodegeneration in PD. On the basis of current evidence, we intend to elucidate the possible role of LBs as triggers and/or markers of disease progression in PD. We present evidence for the morphogenesis of brain stem and cortical LBs, the role in neuronal cell death mechanisms, which seem to be correlated with the adhesion of LBs to and finally disruption of their inner neuronal membrane. Taken as such, LBs would be salient killers of nerve cells. However, they may also play a neuroprotective role in the early phases of neuronal pathology (LBs as a spectator), yet harmful to neuronal stability in later stages of LB development. Generation of LB pathology in the periphery (early subclinical Braak stage) might be due to reactive oxygen species (ROS) due to (chronic) bacteria-induced and/or otherwise intestinal inflammation, both leading to alpha-synuclein structural changes, oligomerization, seeding and propagation in a prion-like mechanism. If so, LB generation is a secondary process following ROS/inflammation pathology. Therapeutic implication based on LB pathology include drug development to inhibit protein misfolding, templating and transmission or vaccination against LBs, neuron regeneration strategies, anti-inflammatory and anti-biotic drugs as well as nutritional specialities to prevent intestine intoxications. In conclusion, evidence suggests LBs to be secondary hallmarks of PD pathology, induced by ROS/inflammation or other pathological triggers able to modify protein (alpha-synuclein) steric/chemical properties. Therapeutic strategies based on LB pathologies are devoted to reduce neuron cell death mechanisms in their time course and severity.