ISSN (Print): 1871-5273
ISSN (Online): 1996-3181
Volume 19, 10 Issues, 2020
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ISSN (Print): 1871-5273
ISSN (Online): 1996-3181
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Special Issue Submission
"This journal is the definitive source for the most meaningful and critical information available on CNS drug targets and progress both in industrial and academic based neurodegeneration research."
Rudolf E. Tanzi
Harvard Medical School, USA
Recent Advancements in the Chemistry of Novel CNS Drugs: A Step Towards End of Illness
Guest Editor(s): Pooja Chawla, Faheem Hyder Pottoo, Mohd. Javed Naim Naim, Md Noushad Javed
Submit Abstract via Email
Brain Imaging and Automatic Analysis in Neurological and Psychiatric diseases
Guest Editor(s): Yu-Dong Zhang, Ti-Fei Yuan, Zheng-Chao Dong
Tentative Publication Date: May, 2016
Submit Abstract via Email
Editorial Advisory Board Members Special Issue
Guest Editor(s): Stephen D. Skaper
I recommend CNS Neurological Disorders & Drug Targets to neuroscientists and practicing neurologists. The papers published on this platform are always of sufficient merit and quality. It maintains the highest standards of peer review, preserving the integrity of science.
Abdelrahman Ibrahim Abushouk (Faculty of Medicine, Ain Shams University, Cairo, Egypt.)
36 Abstract Ahead of Print are available electronically
41 Articles Ahead of Print are available electronically
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 . 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 . 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 . 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 . 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 .
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,
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 .
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.  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.  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.  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.  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.  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  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).
Although the impact of metabolic disorders (obesity, diabetes etc.) on physical health is widely
recognized, a recent and growing body of research showed that this pathology is also associated
with cognitive impairment, deficits in learning, memory and executive functioning, and
increased incidence of neuropsychiatric disorders. On the other hand, stressful life events deeply
impact on brain and bodily function and, in addition to representing major risk factors for
neuropsychiatric disorders, also influence energy metabolism and feeding control. Indeed, while
acute stress rapidly induces hyperglycemia, prolonged increased glucocorticoids stimulate
appetite and increase gluconeogenesis and fat storage. Considering the global aging of world
population and the increased prevalence of metabolic disorders and Neuropsychiatric Disorders,
a better comprehension of pathophysiological mechanisms of these disorders in aging has
become crucial for better prevention, diagnosis and treatment. Moreover besides above, recent
evidence has implicated neuroinflammation and endoplasmic reticulum (ER) stress as
components of a novel form of neuronal metabolic stress that develop in neurological disorders
and peripheral nervous system dysfunction over the time. Among the possible underlying
mechanisms whereby both metabolic stress and inflammation impair peripheral as well as higher
neuronal functions and exacerbate neurological disorders. Given the high incidence of
comorbidity and linked etiology, there is urgent need to focus the latest development on the said
Therefore, in the proposed special issue for CNS and Neurological Disorders - Drug Target,
entitled “Metabolic Stress and inflammation: Implication for Treatment of Neurological
Disorders”, we will try to assimilate the available knowledge and understanding on the topic.
The volume will be a very useful treatise to students, basic researchers, and clinicians alike.
In central nervous system (CNS), ion channels, especially potassium channels play important regulatory roles in physiological
processes. Potassium (K+) channels (e.g., voltage-gated K+ channel, calcium-activated K+ channel) can be activated by
membrane potential shift as well as various ligands . K+ channels have widely relationship with CNS diseases. Although
many studies have tried to reveal the effect of K+ channels in CNS diseases [2-5], the underlying mechanisms are not clearly
elucidated, because of the various subfamilies and subtypes of K+ channels.
In physiological condition, K+ channels mainly elicit an inhibitory modulation in central nervous system. Functional deficiency
or expressional down-regulation of K+ channels may enhance neuronal excitability, induce pathological condition, and
thus leads to CNS diseases, such as epilepsy . The suppression of G protein-gated K+ (GIRK) channels are related to the
pathogenesis of Parkinson’s disease, drug addiction, cerebellar ataxia, pain and analgesia . Some K+ channels can also control
the local microenvironment by regulating the extracellular K+ concentration.
This thematic issue has reviewed those research works describing the experimental discoveries, as well as the pathological
effect of K+ channels. In addition, some reviews in this thematic issue also summarized other ion channels, such as Na+ channels,
Ca2+ channels, Cl- channels, transient receptor potential cation (TRP) channels and synaptic receptors (AMPA, NMDA,
GABA receptors), concentrating on their correlationship with K+ channels and CNS diseases.
First of all, Zang K. et al.  and Zhu Y. et al.  focused on the large conductance calcium-activated K+ (BK) channels,
and retrospected the most recent scientific literature on the structure, subunits and locations of BK channels, broadly describing
the functional effects of different BK types on neurons, astrocytes, microglias, oligodendrocytes and smooth muscle cells. After
that, two reviews both concentrated on the modulation of BK channels on the epilepsy, and discussed the possibility of developing
potential antiepileptics targeted on different BK subunits. In the conclusion, the authors optimistically prospected that the
SNPs (single nucleotide polymorphisms) of KCNMA1 and KCNMBs might be the future investigation targets of BK channel
dysfunction, and optogenetic technique could be helpful to suppress the epileptic seizures [6-7].
Gao F. et al.  and Feng X. et al.  more specifically evaluated recent research papers on particular K+ channels. Gao et
al. reviewed those K+ channels in Müller glial cells, which located on the retina and related to the retinal disorders, including
retinal ischemia-reperfusion, diabetic retinopathy, inherited retinal dystrophy, retinal detachment, proliferative vitreoretinopathy
and glaucoma. These retinal K+ channels, such as BK channel, delayed rectifier K+ channel (KDR) and A-type K+ channel,
keep the hyperpolarized potential and contribute to retinal neuronal damage in pathological conditions, which may serve as
potential targets to develop new therapeutic approaches in the future .
Feng et al. reviewed the functions and pathological relations of lysosomal K+ channels with neurodegenerative diseases,
which were also called lysosomal storage diseases (LSDs). Lysosomal BK channel and transmembrane protein 175
(TMEM175), a novel lysosomal K+ channel, have been reviewed in this paper, describing their structure, expression on
lysosomal plasma membrane, modulation effects on Ca2+ signaling and lipid metabolism. Dysfunction of lysosomal BK channels
and TMEM175 elicits LSD-related Fabry disease and Hunter syndrome, which can be rescued by specific K+ channel agonists
Yang J. et al.  reviewed the oxidation of K+ channels in neurodegenerative diseases, such as Alzheimer’s disease (AD)
and Parkinson’s disease (PD). This short review elucidated the damages of different K+ channels caused by reactive oxygen
species (ROS). Oxidation of KV2.1, KV3.4, KV4.3, BK, KATP and organellar K+ channel causes the abnormal features such as
mitochondrial dysfunction, oxidative stress and autophagy compromise, which will result in collapse of intracellular homeostasis
and eventually leads to cell death .
In this thematic issue, Wu X. et al.  and Yan R. et al.  reported their experimental findings on inwardly rectifying
K+ (Kir) channels, both through patch clamp electrophysiological recordings. Wu et al. affirmed that tenidap, an inhibitor of
cyclooxygenase / arachidonate 5-lipoxygenase (COX/5-LOX), served as the opener of Kir2.3 channel and possessed antiepileptic
effect in cyclothiazide induced epileptiform seizures . Meanwhile, Yan et al. reported that Jingshu Keli, a herbal formula
of traditional Chinese medicine (TCM), alleviated the mechanical and thermal symptoms of cervical spondylotic myelopathy
by increasing the phosphorylation level of Kir3.1 . These two works are the only original researches in this thematic issue,
which may enhance the value and significance of this thematic issue, on contributing the advancement of knowledge in K+
Here we mention the TCMs, which represent a large group of medicinal compounds derived from plants and other natural
sources. Those studies of the effects of TCMs on different K+ channels provide new insights on the pharmacognostic aspects to
research K+ channels and CNS diseases. Recent studies have detected several compounds from TCMs that serve as novel K+
channel modulators, for example, curcumin (from Curcuma longa) as blocker to KV1.3, KV1.4, KV2.1 channels [13-15], puerarin
(from Pueraria lobata) as inhibitor to Kir2.1, Kir2.3, KV7.1 channels . In the study from Yan et al., two saponins, ginsenoside
Rb1 (GRb1) and notoginsenoside R1 (NGR1), were also found that acted as an antagonist to Kir currents .
To further investigate the modulation of TCMs on K+ channels and other ion channels, Huang Y. et al. was then provided a
review elucidating the recent studies of TCMs and ion channel . In this review, several TCM herbs and their containing
active ingredients were introduced, including Salvia miltiorrhiza Radix et Rhizoma, Ligusticum chuanxiong Rhizoma, Angelica
sinensis Radix, Panax ginseng Radix et Rhizoma, Panax notoginseng Radix et Rhizoma, Uncaria rhynchophylla Ramulus Cum
Uncis, Scutellaria baicalensis Radix and so on .
Finally, Zhou Y. et al.  and Feng Y. et al.  focused on the voltage-gated Na+ channels (VGSCs) and reviewed their
functional relationship to CNS diseases from recent scientific literature. Zhou et al. discussed the roles of VGSCs in the processing
of sensory information, including auditory sense, visual sense, olfactory sense, tactile sense and taste sense, as well as
related disorders caused by the dysfunction of VGSCs . Meanwhile, Feng et al. retrospected the mutations of VGSC
subunits both on the aspects of genotypes and phenotypes, and introduced specific CNS diseases elicited by VGSC mutations,
especial the epilepsy. In this review, those mutations located on SCN1A (NaV1.1), SCN2A (NaV1.2), SCN3A (NaV1.3),
SCN8A (NaV1.6) and SCN9A (NaV1.7) were described . These two reviews were included into this thematic issue to exhibit
the similarities and differences between Na+ channels and K+ channels, as well as their correlations, in the pathology of
We hope that this special issue represents a valuable contribution to understand the roles of different K+ channels, as well as
other ion channels, in the pathogenesis of CNS diseases like epilepsy.
Cerebellar ataxias (CAs) gather a group of disorders characterized by motor incoordination and impaired
cognitive operations. Rapid developments in novel technologies offer now a real possibility to improve CAs.
Typical examples are molecular targets for stopping degeneration, grafted stem cells to protect degenerating
host cells, and non-invasive cerebellar stimulation to manipulate excitability in a residual cerebellar circuits
in order to improve CAs. In addition, there has been accumulating clinical evidence for therapeutic efficacies
of novel anti-CAs drug such as aminopyridines, and therapies on immune-mediated CAs. Improved
protocols have also been proposed in the field of motor rehabilitation.
These basic and clinical advances have opened a door to a new era where neuroscientists and clinicians will
control the process of cell death and restore impaired cerebellar functions. We aim to gather top reviews to
examine hierarchically the progresses in therapies of CAs in terms of identification of molecular targets,
understanding of cell biology, neural circuits and clinical evidence of effectiveness of new therapies. We will
consider therapeutic strategies not only for the interruption of the disease progression but also for the
restoration of lost cerebellar functions.
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