CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 15, Issue 6, 2016

Alzheimer’s disease (AD) is the most common cause of dementia among the elderly. It is pathologically characterized by diffused extracellular deposits, senile plaques, and intracellular neurofibrillary tangles in the brain, responsible for neuronal dysfunction and cell death. Memory, language and other cognitive functions can be affected to a limited extent in the initial stage called mild cognitive impairment (MCI) or in a more severe and daily life interfering manner in the later stage called dementia. Currently no effective disease-modifying treatment exists for the majority of neurodegenerative diseases. Failure of therapy aimed at affecting beta amyloid pathology has led research to investigate alternative approaches. Recent findings address statins and phosphodiesterase (PDE) inhibitors as compounds able to affect different mechanisms underlying AD. Statins could exert several effects based on their lipid-lowering and cerebral blood flow increasing abilities but also pleiotropic/antinflammatory and neuroprotective properties have been claimed. PDEs act as regulators of intracellular signaling cascades through the control of two second messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate. PDE inhibitors effects in animal models of AD have been promising and their proven safety in clinical use create high expectations for the treatment of AD. In this review, we will report main data and evidence on: 1. Current pathophysiological theories of AD in order to better understand which mechanisms lead to pathological changes and can be affected by therapies; 2. The use of statins and PDE inhibitors in animal models of AD and in humans, analyzing their mechanisms of action.

Alzheimer’s disease is a neurodegenerative disorder leading to dementia. Scientific efforts in the last decade focused mainly on understanding pathophysiology of disease and possible pharmacological approach to alleviate cognitive decline symptoms. Amyloid cascade hypothesis though criticized, remains the leading hypothesis to understand pathogenic mechanisms of cognitive decline. Intriguingly, changes of metabolic activity of cortical neurons are associated with reduced or absent sensitivity to insulin in Alzheimer’s disease brain. Insulin is a multipotent hormone regulating, not only glucose levels, but also cell survival and synaptic plasticity mechanisms of neurons. Replacement of insulin might represent a new strategic approach to counteract neurodegeneration. Here we review most of the available data regarding relationship between Alzheimer’s disease and insulin and propose new direction to deepen our understanding about insulin involvement in the pathogenesis of Alzheimer’s dementia.

The adrenergic system has an important role in normal central nervous system function as well as in brain disease. The locus coeruleus, the main source of norepinephrine in brain, is involved in the regulation of learning and memory, reinforcement of sleep-wake cycle and synaptic plasticity. In Alzheimer’s disease, locus coeruleus degeneration is observed early in the course of the disease, years before the onset of clinical cognitive signs, with neurofibrillary detected at the stage of mild cognitive impairment, preceding amyloid deposition. Thus, in the last years, a great interest has grown in evaluating the possibility of central adrenergic system modulation as a therapeutic tool in Alzheimer’s disease. However, evidences do not show univocal results, with some studies suggesting that adrenergic stimulation might be beneficial in Alzheimer’s Disease and some others favoring adrenergic blockade. In this review, we summarize data from both hypothesis and describe the pathophysiological role of the adrenergic system in neurodegeneration.

In the recent years, classical vascular risk factors have been suggested to play a role also in the development of degenerative dementia. Arterial hypertension has been implicated in the pathogenesis of dementia but no conclusive results have been produced yet; more recently, blood pressure variability (BPV) has been suggested as a more important risk factor for both silent brain vascular lesions and the development of dementia. Blood pressure variability is defined as the variation in blood pressure over time, measured on different time spans and in different ways. We reviewed current scientific literature about the role of BPV in the pathogenesis of dementia, and about the association of abnormal BPV patterns and different forms of dementia. We also suggested some hypothetical pathogenic mechanisms.

Epidemiological studies have suggested that obstructive sleep apnea syndrome (OSAS) may increase the risk of developing cognitive impairment. In patients with Alzheimer’s disease (AD), the prevalence of OSAS is much higher than that expected in cognitively healthy subjects. A deeper knowledge of the pathophysiological link between OSAS and AD and the demonstration that OSAS may directly influence the development of cognitive alterations, would increase prevention and treatment strategies for AD patients. In this article, we discuss the evidence of the association between OSAS and dementia. Moreover, we present data about the functional and anatomic cerebral changes induced by OSAS and the possible effects on cognitive activities and on AD pathogenesis. The possibility to positively influence cognitive impairment by OSAS treatment will be also discussed.

Inflammation is a common response of an individual against either exogenous or endogenous damage. The role of inflammation and of inflammatory cells recently emerged also in the pathogenesis of neurodegenerative disorders. Experimental evidences show how neurotransmitters, besides their role in the synapses, play a modulatory role during immune response. Drugs used for treatment of dementia symptoms are able to increase neurotransmitters levels, and likely to have a modulatory role during immune response. Aim of this review is to discuss the most recent advances on inflammation role during neurodegeneration and also to individuate the potential anti-inflammatory role played by drugs currently used for Alzheimer’s disease treatment.

Hypertension is one of the most important modifiable risk factors of cardioand cerebrovascular diseases, responsible for the development of severe target organ damages. It has been shown that hypertension is associated with an increased prevalence of cognitive decline. It negatively affects the cognitive battery and accelerates dementia. Beside the known detrimental effects of senile hypertension on cognitive performance in the elderly population, previous studies pointed out that young, hypertensive individuals may also suffer from hypertension related changes in their cognitive capacity. Given the high prevalence of hypertension in a wide range of the age pyramid (young individuals, middle aged adults, elderly people), specific cognitive deficits may be present in a large portion of the population putting a heavy burden on society. Better understanding of the underlying mechanisms of hypertension induced cognitive impairment may contribute to the identification of its initiating pathophysiological factors, and serve an earlier diagnosis, intervention at an early stage and prevention of further deficits. Our aim with the current review was to summarize some of the previous findings regarding altered cognitive performance of individuals with hypertension and of those with the most common co-existing risk factors. Furthermore, efforts to explore effects of various antihypertensive medications on cognition and to survey proposed pathophysiological mechanisms of hypertension induced cognitive changes have been made.

Inflammation plays a pivotal role in the ischemia/reperfusion (I/R) injury. Inflammatory response is initiated by the detection of pathogen-associated molecular patterns and/or damage-associated molecular patterns via extracellular and intracellular pattern recognition receptors. The nucleotide-binding oligomerization domain–like receptor family, pyrin domain containing protein 3 (NLRP3) is a component of pattern recognition receptors and serves a vital role in inflammatory response by forming an intracellular multi-protein complex known as NLRP3 inflammasome. There is increasing evidence that NLRP3 inflammasome acts as guardians against host-derived danger materials. The inappropriate activation of NLRP3 contributes to the progression of I/R injury such as myocardial, cerebral, renal, hepatic and retinal I/R injuries. In this review, we summarize the role of NLRP3 in inflammatory response and discuss the relationship between NLRP3 and I/R injury. We also provide insights into new treatment strategies for targeting NLRP3 inflammasome, as well as the upstream and downstream components of NLRP3 in alleviating I/R injury.

Bipolar disorder (BD) affects 1 to 1.5% of the world population and consists of at least one manic episode (or hypomanic) associated with depressive episodes, interspersed with periods of euthymic mood. Recurrent crises lead to significant disability in BD patients, and correlates negatively to social and occupational adjustment. Such disability can be explained by a series of events, such as cortical and altered metabolic activity, impairments in cognitive functions, and in core anatomical structures involved in mood modulation. Therefore, our review aims to provide information on the current research related to the pathophysiology of BD. We will review the cognitive and brain functioning, and biomarkers of BD. The current literature shows that cognitive deficits are commonly observed in all phases in BD patients, independent of a remissive state. These deficits are assigned to functional, structural and metabolic changes, particularly in the pre-frontal cortex region, hippocampus and amygdala, along with the connections between them, as well as decreased baseline brain-derived neurotrophic factor levels or imbalance between pro- and anti-inflammatory cytokines, implying a lower physical ability to reestablish from a stressful stimulus. BD patients effectively present a differentiated pattern of cortical, neuroanatomical and functional responses. It is suggested that physiological processes occur differently in bipolar subjects compared to healthy individuals, affecting behavior and brain function in such patients. Future directions are yet necessary to establish the best way to neutralize or reverse these events.

The single feature of all malformations in cortical development is the clinical association with epilepsy. It has been proven that Sox-1 expression is essential during neurodevelopment and it is reported that Sox-1 knockout mice present spontaneous generalized seizures. Particularly in cerebellum, Sox-1 plays a key role in the Bergmann´s glia (BG) function, which allows the correct function of the Purkinje cells (PC). The targets of PC are the dentate and interpositus nuclei, which form the main cerebellar efferents involved in the physiopathology of epilepsy. Here we present the Sox-1 expression in cerebellum of rats during electric amygdala-kindling. We obtained seizures and once they had 3, 15 and 45 electric stimuli, the animals were sacrificed; the cerebellum was processed for inmunohistochemistry and Western blot analysis was performed to determine Sox-1 expression. Liquid chromatography was performed to examine gammaaminobutyric acid (GABA) and glutamate concentration. According to the literature, a progressive increase was observed in the electrographic and behavioral parameters. We found that Sox-1 expression in 15 and 45-stimuli groups had a statistically significant decrease as compared with controls, while the 3-stimuli group was similar to the control group. The concentration of glutamate was increased in rats with 45 stimuli. We can conclude that Sox-1 expression decreases as the number of seizures increases, and this is probably due to an altered glutamate regulation by a dysfunctional BG. In this way, we can suggest this mechanism as a one possible explanation of how the cerebellum participates in the pathophysiology of epilepsy.

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.

Baicalin (BA) and jasminoidin (JA) exert an additive effect in the treatment of cerebral ischemia, but the underlying molecular mechanism is still unclear. One hundred mice with focal cerebral ischemia/re-perfusion injury were divided into 5 groups: BA, JA, combination therapy (BJ), sham and vehicle. The differentially expressed genes identified by microarray consisting of 374 cDNAs were uploaded into GeneGo MetaCore software for pathway analyses. Networks were constructed to visualize the interactions of the differentially expressed genes. Among the top ten pathways and processes, we found 5, 3, 2 overlapping pathways and 6, 4, 6 overlapping processes between the BA and JA, BA and BJ, JA and BJ groups, respectively; of which 1 pathway and 3 processes were shared by all the three groups. Six representative pathways and 3 processes were activated only in BJ, such as Gamma-secretase proteolytic targets,etc. These BJ representative targeting pathways showed both vertical (e.g. Cytoplasmic/mitochondrial transport of proapoptotic Bid Bmf and Bim) and horizontal (e.g. Endothelin-1/EDNRA signaling) convergences with those of the BA and JA groups based on the upstream and downstream relationship of cerebral ischemia network, which may help to reveal their additive mechanism in the treatment of cerebral ischemia. Network comparison identified important transcription factors that regulated some of the other BJ related genes, such as cMyb and NF-AT. Such a systemic approach based on multiple pathways and networks may provide a robust path to understand the complex pharmacological variations of combination therapies.