CNS & Neurological Disorders - Drug Targets

Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive impairments of cognitive, behavioral and social functions that disrupts an individual’s ability to perform simple daily tasks independently. Aging is a major risk factor for AD and a majority (>95%) of the patients who develop this disease are older. Currently, an estimated 5.8 million people aged 65 years and above are suffering from AD in the USA and this number is projected to increase to 13.8 million by 2050 [1]. AD is the most prevalent form of dementia. Around 47 million people worldwide have dementia and AD accounts for approximately 60-80% of those cases [2]. The clinical manifestations of AD include progressive loss of memory, attentional dysfunction, confusion, disorientation, impaired judgement and decision-making, apraxia, and aphasia. Additionally, other behavioral and psychiatric symptoms such as depression, apathy, anxiety, agitation, delusions, and hallucinations are also common in AD patients [3]. Thus, the disease not only affects the patients but also has far reaching implications on their family members. The most prominent hypotheses supporting the AD pathology are a) Amyloid cascade hypothesis and b) Tau hypothesis. Postmortem studies from the brains of AD subjects demonstrated the presence of amyloid plaques and neurofibrillary tangles (NFTs) which led to the belief that these neuropathological features led to the development of the disease [4, 5]. Amyloid plaques are the deposits of amyloid β (Aβ) peptide present extracellularly in the brain and blood vessels, whereas NFTs are an abnormal accumulation of hyperphosphorylated tau protein present as helical filaments within the neurons. Accumulation of these toxic proteins is suggested to be primarily linked to neurodegeneration in AD. Despite enormous progress in research on AD, the development of drugs that target amyloid and tau biochemical pathways remained unsuccessful clinically in combating AD symptoms. The other hypotheses that are described to support AD pathogenesis include cholinergic hypothesis, excitotoxicity hypothesis, mitochondrial cascade hypothesis, neurovascular hypothesis, and inflammatory hypothesis [6]. Currently, the treatment of AD is limited to a few conventional drugs which provide only symptomatic relief and not cure or halt the progression of the disease. These include cholinomimetic drugs such as rivastigmine, galantamine, and donepezil, which block the enzyme acetylcholinesterase to elevate the extracellular levels of acetylcholine (a neurotransmitter critical for learning, attention and memory). These drugs are well tolerated and provide limited alleviation of cognitive impairments during the early stages of the pathology. Another drug clinically approved for AD is N-methyl D-aspartate receptor antagonist (memantine) that reduces glutamatemediated excitotoxicity and is used in moderate to severe cases to delay cognitive impairments. Peptide-based therapeutics for AD including the neurotrophic factors represent a promising approach; however such drugs are limited to exert the desired beneficial effects due to limited ability to penetrate the blood-brain barrier [7, 8]. Recently, forkhead box class O (FoxO) proteins have been identified as an important target for neurodegenerative disorders. FoxO proteins are essential transcription factors that regulate cellular metabolism, oxidative stress, and apoptosis; these cellular processes are involved in AD pathogenesis [9]. To conclude, long-term effective therapeutic approach for alleviating the cognitive/behavioural impairments and slowing down the progression of AD is an unmet need of the hour. Therefore, rigorous scientific efforts should focus on identifying novel biomarkers that could be used for early detection and tracking the progression of AD, and on identifying neuroprotective targets to develop disease-modifying AD therapeutics. Furthermore, innovative drug delivery and nanotechnology approaches that increase drug permeation through BBB are highly desired to increase the bioavailability and efficacy of AD-related drugs [10, 11].

The diseased or damaged brain has only a limited regenerative capacity which is mainly of functional nature. Effective therapies are still missing for a vast number of pathological conditions of the Central Nervous System (CNS). These usually devastating diseases have a major impact on quality of life and are associated with high socioeconomic costs. Due to increasing life expectancy and a higher prevalence of neurodegenerative and neurovascular pathologies in the elderly population, these disorders will become even more important for our society in the future and there is a need for the development of new, adequate treatment options [1]. This thematic issue provides detailed insights into important neuropathological processes, advances in the development of strategies for disease intervention and highlights the current lack of understanding that still need to be addressed. Parkinson’s Disease (PD) is a neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, eventually leading to a depletion of dopamine in the striatum. The progressive loss of dopamine leads to the cardinal motor symptoms in PD which are resting tremor, bradykinesia, hypokinesia, and muscle rigidity. The selective vulnerability of dopaminergic neurons against various insults, including oxidative stress, is a significant characteristic of age-related degenerative disorders. Up to now, it is not fully understood how aging interferes with the physiology of these affected neurons and how this results in age-related functional deficits. The discovery of the dopamine precursor L-dopa (3,4- dihydroxyphenylalanine) opened a new area for the treatment of the motor symptoms. While L-dopa therapy provides adequate alleviation of the symptoms for several years, the long-term treatment is complicated by progressive disability and development of severe side effects such as dyskinesias, ON/OFF-periods, and hallucinations. In their review, Bogetofte et al. [2] summarize the history and status of L-dopa treatment for PD and carefully discussed advantages and disadvantages as compared to other available therapeutics. PD is generally categorized as a movement disorder. More recently however, it has been recognized that PD patients suffer a range of non-motor symptoms. These include neuropsychiatric symptoms which are likely associated with the dysfunctional nondopaminergic pathways occurring in PD. In this respect, Impulse Control Disorders (ICD) like hypersexuality and compulsive use of dopaminergic medication have a negative impact on the quality of life of both the patients and their relatives. Notably, there is a lack of defined strategies for the management of ICD and the only acclaimed strategies are a reduction or discontinuation of dopamine agonists and levodopa, leading thereby often to a deterioration of motor symptoms. Subthalamic deep brain (STN-DBS) stimulation has been used over the past years as a safe and effective treatment, mainly in younger patients with disabling motor complications due to levodopa treatment. The situation in patients with ICD, however, is not yet perspicuous. In their review, Amstutz et al. [3] describe the outcome of STN-DBS based on retrospective, prospective and randomizedcontrolled studies. They conclude that ICDs improve after STN-DBS in most patients and that persisting new-onset ICDs induced by STN-DBS are rare, however, the underlying mechanisms need to be further investigated. Importantly, they propose that other non-motor symptoms, e.g. sleep disorders, depression and apathy, should also be used as secondary outcome parameters in studies addressing the impact of STN-DBS as a management strategy for ICDs. In vitro studies on dopaminergic neurons are indispensable for drug screening and the investigation of the mechanisms of neurodegeneration in PD. Accordingly, the neuroblastoma cell line SH-SY5Y is frequently used for this purpose because of the ease of handling the human origin. Importantly to note, a detailed description of the differentiation protocols is missing in most of the studies and there is a lack of consensus about the phenotypic traits obtained. A comprehensive and quantitative evaluation of the modulation of phenotypical markers, however, is essential to allow for a proper interpretation of the results. Moreover, in order to obtain a high number of cells with a dopaminergic phenotype an optimized differentiation protocol is needed. In their experimental article, Ducray et al. [4] describe a thorough phenotypic and morphological characterization of SHSY5Y in relation to different differentiation protocols. The authors report an enormous variation of marker expression depending on the culture conditions tested. These results are of great importance for pharmacological and disease modelling studies. Scheller Nissen et al. [5] in depth describe the current knowledge, disease mechanisms, diagnosis and treatment of Autoimmune Encephalitides (AE). AE comprise an astounding number of diseases characterized by antibodies against neuronal synaptic and cell surface antigens. Many of the disease-causing antibodies present as limbic encephalitis which goes along with memory impairment, psychiatric features and epileptic seizures. In their review, the authors focused mainly on the two major subtypes, i.e. NMethyl-D-Aspartate receptor encephalitis and voltage-gated potassium channel complex encephalitis as the treatment options are basically the same regardless of the antibody type. While much information on clinical features, pathophysiology and treatment has been gathered over the last years, present treatment regimens are still based on knowledge from other antibody-mediated neurological disorders. Hence, they propose that multicenter randomized clinical trials need to be conducted to find new optimal treatment procedures. This might also be relevant for the discovery of biomarkers to monitor the efficacy of the therapy applied. The formation of fibrotic scars is a physiological response to tissue injuries in the CNS and the Peripheral Nervous System (PNS). Current evidence indicates that fibrosis is involved in the inhibition as well as in support of repair mechanisms in the nervous tissue. In their review, Ghosh et al. [6] illustrate the cellular and molecular mechanisms underlying the development of fibrosis which follows spinal cord and peripheral nerve injuries. A better understanding of the cascade of events associated with fibrosis would enable to steer the tissue response to injuries towards restorative processes. This knowledge is thus essential to improve the efficacy of therapeutic interventions for nerve regeneration in CNS and PNS. Glioblastoma Multiforme (GBM) is considered the most aggressive and common primary central nervous system tumor in adults. Unfortunately, despite the advances in surgical procedures, radiotherapy, and chemotherapy GBM remains an incurable disease with remarkably poor prognosis. A variety of innovative treatments have been introduced to meet the demand to improve current therapies and increase patient survival. In this context, Tumor Treating Fields (TTF) is a promising therapeutic tool for the treatment of GBM. Despite TTF has entered the clinical practice, its mechanisms of action are not entirely clear. Increasing evidence suggests that TTF exert a variety of effects in addition to the inhibition of mitotic spindles formation and cell membrane rupture in the highly proliferating GBM cells. In their review, Kissling and Di Santo [7] have screened the literature addressing the mechanisms of action of TTF and emphasized the effects on cell physiology which have so far remained in the background but are fundamental to overcome the resistance of GBM to therapies. The resulting message is that future studies on TTF should also focus on the effects on immunity, on cell migration and angiogenesis inhibition. Harnessing these effects especially in combination with current treatments as chemotherapy or radiotherapy might lead to the development of new therapeutic approaches for GBM. Adequately characterized model systems and clinical studies are needed to improve the knowledge on the mechanisms and underlying causes of neuropathological disorders. Given that most interventions only start when the neuropathological processes are already advanced, a detailed analysis of potential biomarkers needs to be assessed, allowing for earlier interventions. Future research involving international multicenter randomized clinical trials are warranted to elucidate optimal treatment regimens.

Neuroinflammation associated with activated glia has been considered as a driving force in the pathogenesis of various neurodegenerative disorders, including Alzheimer Disease (AD), for three decades. On the other hand, for more than half a century, the monoamine hypothesis has been regarded as the most likely cause of the archetypal endogenous psychoses, schizophrenia and major depression. However, accumulating evidence suggests that neuroinflammation may play a significant role in the pathogenesis of endogenous psychiatric as well as neurodegenerative disorders. Recent positron emission tomography studies have revealed that microglia are in a neuroinflammatory activation state in schizophrenia [1, 2] and major depression [3, 4]. Therefore, neuroinflammation associated with activated glia appears to be a common driving force for both neurodegenerative disorders and endogenous psychoses (hereinafter referred to as neuropsychiatric disorders in this special issue).

Furthermore, various alterations in gene expression and/or serum levels of growth factors, such as brain-derived neurotrophic factor, epidermal growth factor, Fibroblast Growth Factors (FGFs), Insulin-like Growth Factor (IGF)-1, erythropoietin, and Nerve Growth Factor (NGF), have been implicated in the pathogenesis and clinical manifestation of schizophrenia and major depression [5]. FGFs and IGF-1 are glial growth factors. It has been suggested that a functional deficiency of glial growth factors and growth factors produced by glial cells (e.g., NGF and glutamate) may lead to synaptic destabilization and cause schizophrenia [6].

Based on the findings mentioned above, glia and glial growth factors could be new therapeutic targets in neuropsychiatric disorders. In fact, in an animal model presenting schizophrenic and depressive behavior, Electroconvulsive Treatment (ECT), that is considered as the last treatment option with clinical efficacy for drug-resistant psychiatric disorders, has been shown to attenuate both microglial activation and astrocytic activation with amelioration of the abnormal behavior [7, 8]. ECT has also been shown to increase mRNA expression of both FGF2 (also referred to as basic FGF) and NGF [9]. This issue has collected the latest findings on these aspects and discusses the potential of modulating glial activation and the expression of glial growth factors for antipsychotic and antidementia therapies.

Several intracellular stress proteins have been shown to exert extracellular effects that are anti-inflammatory or favor the resolution of inflammation. These molecules were defined as Resolution-Associated Molecular Patterns (RAMPs) by Shields et al. in 2011 [10]. In the first article of this special issue, Wenzel et al. have summarized the available evidence for the roles of RAMPs in physiological processes within the Central Nervous System (CNS) and neurodegenerative diseases. RAMPs include cardiolipin, prothymosin α, binding immunoglobulin protein, Heat Shock Protein (HSP) 10, HSP 27, and αB-crystallin. They all are endogenous molecules. RAMPs are released by damaged or dying CNS cells into the extracellular space where they can signal in autocrine/paracrine fashion by interacting with glial cell receptors and thus convert glial cells from CNS homeostasissupporting functional states into adverse activation states. Accordingly, the authors point out that clarifying the molecular mechanisms engaged by RAMPs could lead to the identification of novel therapeutic targets on glial cells useful against neuroinflammatory disorders, including AD.

In the second article, Nakanishi et al. focused on the close relationship between periodontitis, a common chronic inflammatory disease, and AD. It has been demonstrated that lipopolysaccharide of P. gingivalis (Pg), a major pathogen of periodontal disease, activates microglia with resultant neuroinflammation and increased Aβ accumulation in neurons, and that these ADlike pathological changes are mediated by cathepsin B [11]. In addition, gingipains, and toxic proteases produced by Pg have been shown to induce microglial migration/activation associated with inflammatory response in mice [12]. Based on these findings, the authors emphasize that the inhibition of microglial cathepsin B or Pg gingipains could be the most promising therapeutic treatment for sporadic AD. In fact, COR388, an inhibitor of lysine-specific gingipain K, is currently in the middle of clinical phase II/III trials in the United States.

In the third article, Hayashida et al. investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. They chose FGF2 since it is a multifunctional growth factor that plays a pivotal role in the prosurvival, pro-migration and pro-differentiation of neurons [13] and schizophrenia can be considered as a neurodevelopment disorder. They found that serum FGF2 levels in Gunn rats were significantly lower than those in the normal strain Wistar rats. Interestingly, this finding is opposite to the results of previous clinical studies, in which, regardless of whether schizophrenic patients were receiving medication or not, they showed significantly higher serum levels of FGF2 than did normal controls [14, 15]. Further studies are obviously required to resolve this discrepancy.

Last but not least, the editor would like to thank the authors for their great contribution to this special issue and the anonymous reviewers for their insightful comments. Sincere acknowledgements are also extended to Dr. Edith G. McGeer for her kind support and to Mr. Faizan Hakeemi for publication management.