CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 16, Issue 4, 2017

Background & Objective: Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Conclusion: Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.

The role of dopamine in sleep-wake regulation is considered as a wakefulness-promoting agent. For the clinical treatment of excessive daytime sleepiness, drugs have been commonly used to increase dopamine release. However, sleep disorders or lack of sleep are related to several dopaminerelated disorders. The effects of dopaminergic agents, nevertheless, are mediated by two families of dopamine receptors, D1 and D2-like receptors; the first family increases adenylyl cyclase activity and the second inhibits adenylyl cyclase. For this reason, the dopaminergic agonist effects on sleep-wake cycle are complex. Here, we review the state-of-the-art and discuss the different effects of dopaminergic agonists in sleep-wake states, and propose that these receptors account for the affinity, although not the specificity, of several effects on the sleep-wake cycle.

Neurodegenerative diseases, namely Alzheimer’s disease and Parkinson’s disease represent a deleterious impact worldwide. Despite extensive preclinical and clinical research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacological intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl- D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochemicals may represent beneficial drug candidates for the treatment and prevention of Alzheimer’s and Parkinson’s disease.

Background: Major depressive disorder (MDD) is associated with high mortality and morbidity rates, and currently, approximately 340 million people worldwide suffer from depression at some point in life. In view of the growing socio-economic and clinical impact, several studies have focused on the etiopathology of MDD, suggesting that not only the monoaminergic system but also other brain mechanisms may be involved in the pathophysiology of MDD. Recent studies have shown a link between inflammation and MDD and have also demonstrated that antidepressants and antiinflammatory drugs can act to reduce inflammation, thereby improving depressive symptoms. Animal models of depression are indispensable for studying the pathophysiology of this disorder and new treatments for it. Further, studies have shown that rodent models of depression are also associated with elevated levels of inflammation in the periphery and brain. Objective: This review will highlight the role of immune inflammation in MDD and the significance of immune system modulators with antidepressant effects in the treatment of MDD, based on studies using animal models of depression.

Amyloid based hypothesis led to develop biomarkers oriented diagnosis of neurodegenerative dementias. Among them biomarkers for AD, the most diffuse form of dementia, are currently the unique available for scientific and diagnostic purposes. CSF biomarkers like Amyloid beta 42, total tau and phosphorylated tau levels can be easily evaluated in individuals suffering from cognitive decline, to diagnose or exclude AD type dementia, since early stages. Moreover, their analysis gave the opportunity to better understand cognitive decline patho-physiology during aging. Experience from their use and analysis however showed a high degree of variability due to the great heterogeneity of AD on one hand, the presence of isolated CSF biomarker changes that are not to be considered of AD type and deserve a clinico-pathological classification on the other. Aim of this review is to offer the knowledge about CSF biomarker’s use in clinics.

The opioid system has been elucidated as a potential target for therapy in a variety of neurological disorders including stroke. Delta opioid receptors have been revealed to pose an especially compelling biological function for new neuroprotective therapies. Two distinct therapeutic mechanisms have been characterized for delta opioid receptors, namely, these receptors aid in maintaining ionic homeostasis and initiate endogenous neuroprotective pathways. Specific agonists of delta opioid receptors, such as (D-Ala2, D-Leu5) enkephalin (DADLE), have displayed the ability to promote neuronal survival and mitigate apoptotic pathways. These findings have led to a significant amount of research on this molecule's potential as a neurotherapeutic. At the forefront of these efforts has been investigation into DADLE’s ability to protect neurons and glial cells following ischemia. Additionally, current research is attempting to reveal the dynamic neuroprotective mechanisms that mediate DADLE's therapeutic benefits. This review article discusses the scientific evidence supporting the use of delta opioid family of receptors and ligands as a promising target for therapeutic intervention in neurological disorders, with emphasis on stroke.

Background: Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. Objective: To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. Method: A literature search was conducted in PubMed for ‘PD treatment’, ‘MAO-B inhibitors’, ‘selegiline'’, ‘rasagiline’, ‘safinamide’ and ‘clinical trials’ with ‘MAO-B inhibitors’ in ‘Parkinson’ disease'. Results: MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Conclusion: Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD.

Treatment resistant depression (TRD) and suicidal behavior are among the most important public health problems and are commonly associated with significant disability and psychosocial impairment. Although there have been recent advances in identifying the neurobiological correlates of these complex conditions, their pathophysiology still remains unclear. Compared to non-suicidal subjects, higher mean concentrations of inflammatory mediators have been found in both the periphery and brain of individuals at risk for suicide. Several lines of evidence suggest that neuroinflammation is accompanied by a dysregulation of the kynurenine pathway (KP) in both TRD and suicidal individuals, resulting in an imbalance of neuroactive metabolites. In particular, neuroinflammation may trigger an increased production of the N-Methyl-D-aspartate (NMDA) receptor agonist quinolinic acid and a concomitant reduction of neuroprotective metabolites, potentially causing downstream effects in glutamatergic systems resulting in depressive symptoms and suicidal behavior. This systematic review of the current literature is mainly aimed to summarize the most important evidence pertaining to KP metabolism abnormalities in TRD and suicidal behavior. Targeting the KP enzymes may provide innovative approaches in the management of both TRD and suicidality.

Suicide risk is a major cause of death among patients with schizophrenia. Death by suicide has been reported in approximately 5% of schizophrenia patients although this figure appears to be an underestimate of the problem. A number of risk factors are routinely reported as associated with suicide risk among these patients, some of which are modifiable by targeted therapeutic strategies. Clozapine is the only compound that gathered evidence as an effective treatment for reducing suicide risk in schizophrenia. Long-Acting Injectable Antipsychotics (LAIs) have a range of advantages in terms of efficacy, safety and tolerability in the treatment of schizophrenia, and one area of interest is whether LAI-treatment may decrease suicidality by indirectly acting on a range of risk factors for suicide specific to schizophrenia patients. This background encouraged the present review of research pertaining to LAIs in relation to modifiable risk factors for suicide in schizophrenia. We viewed our task as gathering, speculating and critically appraising the available research relevant to the topic, with the aim of formulating a hypothesis to be tested with further research.

Dysfunction of synaptic neurotransmitter release is closely involved in the pathogenesis of various central nervous system diseases. Synaptic vesicle glycoprotein 2A (SV2A) is a membrane protein specifically expressed in synaptic vesicles and it modulates action potential-dependent neurotransmitter release in the brain. Since 1) SV2A-knockout mice exhibit severe convulsive seizures, 2) SV2A expression in the brain is reportedly altered in various epileptic disorders both in animal models (e.g., kindling and genetic models) and humans (e.g., intractable temporal lobe epilepsy and focal cortical dysplasia) and 3) SV2A serves as a specific binding site for the antiepileptic drug, levetiracetam and its analogues, it is considered that SV2A is involved in the pathogenesis and treatment of epilepsy. In addition, a recent clinical study demonstrated that a missense mutation in the SV2A gene caused intractable epilepsy with involuntary movements and developmental retardation, illustrating a causative role of SV2A dysfunction in epilepsy. Although the functional mechanisms of SV2A in regulating epileptogenesis remain unknown, studies using animals carrying the Sv2a missense mutation showed that the dysfunction of SV2A preferentially disrupts action potential-induced γ-aminiobutyric acid (GABA), but not glutamate, released in the limbic regions (i.e., hippocampus and amygdala) and markedly facilitates kindling epileptogenesis. All these evidences indicate that the SV2A-GABAergic system plays a crucial role in modulating epileptogenesis and encourages research on the novel antiepileptic agents which enhance SV2A function.

Background: Evidence has implicated the translocation of commensal Gram-negative bacteria (Gram-B) due to leaky gut in the pathophysiology of depression and physio-somatic symptoms (e.g. fatigue, pain, irritable bowel syndrome, malaise, etc.). In addition, the leaky gut may contribute to immune- inflammatory activation and oxidative stress. This study investigated whether bacterial translocation is associated with perinatal depression and anxiety scores and with prenatal physio-somatic symptoms and immune-inflammatory biomarkers, including the tryptophan catabolite (TRYCAT) pathway. Method: Data were collected in pregnant women at the end of term (T1) and 4-6 weeks after delivery (T2) as well as in non-pregnant controls. We examined the associations between serum IgM/IgA responses to Gram-B at the end of term and depression (Edinburgh Postnatal Depression Scale -EPDS) and anxiety (Spielberger’s State Anxiety Inventory -STAI) symptoms. Results: Levels of C-reactive protein, zinc, haptoglobin, hematocrit and IgA/IgM responses to 9 TRYCATs were also measured. No significant associations of the IgA/IgM responses to Gram-B with prenatal depression and anxiety were observed. Increased IgA/IgM responses to Gram-B predict higher levels of haptoglobin, hematocrit and TRYCATs, in particular quinolinic acid and the quinolinic acid / kynurenic acid ratio. IgA responses to Gram-B were significantly lowered in pregnant women compared to age-matched non-pregnant women, while IgM responses were significantly elevated in participants with alcohol consumption. Physio-somatic symptoms at the end of term were significantly associated with IgM responses to Klebsiella pneumonia. Postnatal anxiety was significantly predicted by IgA responses to Pseudomonas aeruginosa. Conclusions: Our findings suggest that pregnancy may protect against bacterial translocation, while alcohol use may increase bacterial translocation. The results suggest that end of term mucosa-derived immune responses to Gram-B contribute to immune activation, physio-somatic symptoms at the end of term and postnatal anxiety. Highlights: • Immune responses to Gram - Bacteria associate with physio-somatic symptoms in pregnancy. • IgA responses to Pseudomonas aeruginosa predict anxiety symptoms after delivery. • Pregnancy may have a protective effect against bacterial translocation. • Alcohol use increases leaky gut and bacterial translocation.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a complex interplay between peripheral and central inflammatory and oxidative stress pathways. Objective: To investigate immune-inflammatory and oxidative stress pathways in relation to iron metabolism in peripheral blood of PD patients and healthy controls. Method: We recruited 56 healthy individuals and 56 PD patients in stages 1-3 of Hoehn and Yahr Scale. Plasma haptoglobin (Hp), homocysteine, interleukin 6, soluble interleukin 6 receptor, iron (Fe), ferritin, total iron binding capacity, transferrin (Tf), soluble transferrin receptor (sTfR), malondialdehyde (MDA) and paraoxonase 1 (PON1) were measured. Results: PD was associated with significant changes in Tf (lowered), sTfR, ferritin, Hp, interleukin 6 and MDA (all increased) levels, while there was a trend towards a negative association with PON1. Logistic regression showed that the most significant biomarkers of PD were MDA, sTfR, Hp and ferritin. Moreover, Fe levels were negatively associated with Hp and positively with PON1, total iron binding capacity and Tf, while ferritin and sTfR were positively associated with MDA levels. Conclusion: Our study indicates a state of systemic inflammation and oxidative stress in PD patients coupled with alterations in Fe metabolism. Chronic inflammation and oxidative pathways in PD may in part determine changes in iron metabolism. New drug treatments for PD should target inflammatory and oxidative stress pathways and iron metabolism as well.

Background: Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action. Method: Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test. Results: The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action. Conclusion: Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.

Background: The aging world population had led to an increase in the prevalence of Alzheimer’s disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. Method: PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. Results: The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. Conclusion: The concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

Objective and Background: To evaluate whether increased levels of high-sensitivity C- reactive protein (hs-CRP) observed in individuals with bipolar disorder (BD) compared to healthy controls (HCs) could be influenced by a previous exposure to early life stress (ELS) independently from other explanatory or background variables, including age, body mass index (BMI), and the presence of cooccurring mental disorders. Method: In this case-control study, we included 142 healthy controls and 92 bipolar I and II patients. The Childhood Trauma Questionnaire was administered in a subset of 30 female patients with BD and 31 female HCs, and plasma hs-CRP was measured in all subjects. Multivariable models adjusted the data for the possible confounding variables. Results: Serum hs-CRP levels were significantly higher in patients with BD compared to HCs. However, after controlling for BMI, these differences were no longer significant. Around 55% of the variance in hs-CRP was explained by cumulative and independent effects of age, BMI and childhood trauma, especially sexual abuse. Conclusion: Our results show that increased hs-CRP levels in BD patients are more related to childhood trauma, especially sexual abuse, age and BMI than to a diagnosis of BD per se. These data suggest that peripheral inflammation may underpin the well-known detrimental effects of childhood maltreatment and obesity in the course of BD. Hs-CRP data are difficult to interpret if they are not adjusted for effects of BMI and age.