ISSN (Print): 1871-5273
ISSN (Online): 1996-3181
Volume 20, 10 Issues, 2021
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ISSN (Print): 1871-5273
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"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
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.)
16 Abstract Ahead of Print are available electronically
55 Articles Ahead of Print are available electronically
If we look around ourselves, there are numerous granted bounties by the Creator which are often overlooked, for example,
air, water, eyesight, hearing, cognitive power of thinking, power of taste buds, touch and imagination. From a memorable
memory to a sincere smile from a friend, we feel the positive energy within. How it changes one’s mood and behaviour? When
looking at flowers, feeling the morning breeze or hearing the falling water we can recognize the bounties of the Creator and use
them in a way to please our Creator through taking care of His creations, and mankind. Inside our body, within the cells and the
organelles, we can see numerous systems working to maintain the health of the body. Many incentives of nature are outside our
bodies such as the sun, stars and galaxies. One bounty is physical health whilst the other is our spiritual health. How precious is
the value of health, we can ask from the sick especially those in the last stage with a poor glimpse of recovery. Albeit, when the
body is healthy it can function and work systematically requiring a good sleep at night with sufficient oxygen. Our parasympathetic
system is over dominated by the sympathetic system in such a way that our heart rate reduces and our mind slows down.
Our soul is partially divided, one with our physiological body whilst the other part is returned to a temporary phase of its origin.
When morning comes they unite as we become a fresh walking, talking, living body ready for the productivity of a new day. So
good sleep of 7/8 hours is also a good gift of the Creator, while in some cases, if someone has a sleep disorder such as sleep
apnea, the level of oxygen drops causing sleep disturbance. In this special issue, expert researchers in the field of sleep disorders
highlight the scientific approach in sleep disorders particularly in neurodegenerative disorders such as Parkinson and Alzheimer's
Usually, most people, who have sleep disorders, do not come forward to get treatment; therefore, around 15 % of the population
are registered for a diagnosis. It has been shown to increase with age. Different types of comorbid sleep disturbances frequently
complicate a wide variety of neurologic disorders, and this is mainly related to the damage of neural structure in sleepwakefulness
regulation, pain caused by disease or lesion, reduction of movement and treatment. Sleep disorders can also be an
early or even main symptom of various neurological diseases, for example, Rapid eye movement sleep Behavior Disorder
(RBD) and Obstructive Sleep Apnea (OSA) in AD. It can occur before the occurrence of neurological diseases, affect the disease
process, daytime function, quality of life, morbidity and mortality of the patients. The occurrence of some types of sleep
disorders could be useful in the early diagnosis of many neurological diseases. A deeper contribution of OSA to AD pathogenesis
is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture,
intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All
of these could increase the risk for AD, rendering OSA as a potentially modifiable target for AD prevention. Treatment of
comorbid sleep disturbances may improve the symptoms of many neurologic diseases. Significant progress has been made in
the diagnosis, clinical types and neuropathophysiological mechanisms of sleep disorders in neurological diseases. Despite these
primary observations, it is still insufficiently considered in clinical practice, and treatment options are limited. Therefore, the
purpose of this special issue is to present high-quality reviews and research articles on the possible disease connections and the
potential therapeutic targets between sleep disorders and AD.
Hopefully, this special issue will help researchers to develop therapeutic drugs for sleep disorders. We are thankful to all authors
who submitted their articles in this Special Issue, and reviewers, who secured their time in providing valued feedback to
improve the submitted manuscripts.
A huge number of individuals today use herbs as drugs alongside medicine and non-physician recommended medications,
huge numbers of these herbs can potentially interact with other drugs, causing hazardous adverse effects and /or diminished
advantages of prescription. It ought to be comprehended that herbal drugs contain multiple active compounds in different percentages
which can change the enzymatic frameworks, transporters and additionally the physiologic processes. Assessment of
herbal drug interaction is difficult because of inconstancy in herbal drug composition and meagre information of active constituent
pharmacokinetic. These restrictions are further bewildered by the differing points of view concerning herbal product regulation.
A basic assessment of certain pharmacokinetic HDI is needed to settle on educated choices in regards to patient safety.
The expanding comprehension of HDPKI will pay attention to potential interactions according to Ahmed et al. report .
Conventionally cardiac biomarkers are recognized as a significant tool to investigate the presence or progression of various
cardiovascular diseases. However, in recent years’ data from several clinical trials have successfully sorted out the utility of
cardiac biomarkers in diseases that are not primarily regarded as “cardiac diseases”. Results of freshly published trials have
endorsed the use of cardiac biomarkers in a variety of diseases that vary from Chronic Kidney Diseases (CKD) to Community-
Acquired Pneumonia (CAP), central nervous system disorders and several others. Alzheimer’s disease is also one of the CNS
conditions where measuring cardiac biomarkers are useful. Cardiac biomarkers can be helpful in two ways. Firstly, to assess the
secondary involvement of the heart during the progression of the primary disease. Secondly, they can be useful in the diagnosis
and prognosis of the primary condition itself. Khan and Kamal had collected encouraging results from recent studies and have
shown the importance of the most widely recognized cardiac biomarkers. These markers include from the classic ones such as
natriuretic peptides including B-type Natriuretic Peptide (BNP) or N-terminal pro-B- type Natriuretic Peptide (NT-proBNP) natriuretic peptides including B-type Natriuretic Peptide (BNP) or N-terminal pro-B- type Natriuretic Peptide (NT-proBNP)
and cardiac Troponin (cTn) to newer biomarkers such as the soluble Source of Tumorigenicity 2 (sST2) and Galectin-3 (Gal-3).
The results showed that cardiac biomarkers carry significant importance in making diagnosis and prognosis of AD, stroke,
pneumonia, and many other conditions and wider recognition and use of these biomarkers is expected in the future .
Nature has bestowed mankind through additional resources Natural Products (NPs) on earth with water. However, NPs have
a significant function in the avoidance of disease by boosting health in humans as well as animals. These NPs have been scientifically
acknowledged to have a range of biological characteristics like antioxidant, anti-inflammatory actions. Both in vitro
and in vivo studies have recognized the convenience of NPs in different preclinical models of neurodegenerative disorders.
Moreover, most NPs comprise phytoconstituents, including polyphenolic antioxidants; originate in herbs, fruits, nuts, vegetables
as well as in marine with freshwater flora. These phytoconstituents might actively repress neuro-degeneration and recover
memory as like cognitive actions of the brain. Moreover, they are well recognized to participate in an essential position in the
prevention like healing of dissimilar neurodegenerative diseases, like AD, Parkinson’s disease, epilepsy, and additional neuronal
disorders. In general, the large-scale neuro-pharmacological actions of NPs have been familiar owing to the consequence
of also the inhibition of inflammatory processes, or the up-regulation of various cell endurance proteins or a mixture of them
together. Owing to the shortage of human studies on neuroprotective belongings of NPs, Rahman et al., highlighted a variety of
documented actions of NPs in vitro and in vivo preclinical models and their possible neuro-protection applications by the accessible
awareness in their writing .
Dementia is a diverse category of a chronic and progressive disorder, which is commonly associated with loss of memory,
difficulty in judgment, impaired language, cognitive impairment, and various other symptoms that affects a person’s daily routine
life and social life . Autophagy is a necessary process of cellular protein clearance mechanism, which is dependent on
lysosomes. It is a basic physiologic process that performs the crucial function of maintaining cellular protein homeostasis. The
autophagic dysfunction in dementia further complicates the disease by hampering the degradation and removal of abnormal
pathogenic proteins. To understand autophagic dysfunction, it is essential to know the genetics of autophagy as well as the mutations
which cause autophagic dysfunction. Kumar et al. shared their understanding at the genetic level to define the relationship
between dementia and autophagic dysfunction for developing potential remedies for the treatment of dementia .
Alzheimer’s disease, characterized by abnormally phosphorylated tau, PHFs, NFTs, deregulated mTOR, Aβ deposits, is a
multifactorial disease with sleep disorders being one of its major causative agents . Mueed et al. reviewed the literature and
have tried to decode the existence of positive feedback, reciprocal and a bidirectional relationship allying between sleep disturbances
and AD. Much light has been thrown on the role of tau pathology and amyloid pathology in sleep pathology, its association
with AD pathology and the role of melatonin in regulating sleep disorders and AD. The neuroprotective action of melatonin
via inhibiting tau hyperphosphorylation and Aβ deposition has also been pondered upon. Moreover, astrocytes involvement
in aggravating AD has also been highlighted. Several therapeutic approaches aimed at improving both sleep disorders and
AD had been duly discussed such as administration of antidepressants and antihistamines, immunotherapy, metal chelators,
melatonin supplementation, light therapy, and physical activity .
Lack of sleep generated many disorders bruxism is one of them. It has affected almost 31% of the world's population. Heyat
et al. determined the volume of the research conducted on bruxism and created a database . They highlighted open research
questions and critical issues for further research commitments and communications by designing a comprehensive and very
perception-based picture of bruxism disorder. That work used three methods such as systematic mapping process, network visualization,
and literature review by using some software such as VOSviewer, MATLAB, and MEGA-X to analyze the data related
to the understanding of bruxism disorder from dental to psychological concepts, from engineering detection to clinical
treatment, and from temporomandibular disorder to biological genes. They concluded that Bruxism is a sleep, neurological, and
dental disorder .
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by sleep, behavioural, memory, and cognitive
deteriorations . Sleep Disturbance (SD) is a major disease burden in AD which has a reciprocal relationship with AD pathophysiology.
It aggravates memory, behavioural, and cognitive complications in AD. Different studies found that melatonin
hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the major sleep-regulating hormone and a potent antioxidant
with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous
melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been
conducted so far that assessed the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that
melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of
melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for
the discrepancies between the studies. Larger trials with longer durations and higher dosage forms and studies including bright
light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy
of melatonin to treat SD in AD .
While in the previous volume (I) there were seven articles, which covered various aspects, such as the following: 1. A bibliometric
analysis in sleep disorders research from 1945 to 2020 ; 2. Modifiable risk factors associated with AD with special
reference to sleep disturbance ; 3. Cellular and molecular mechanisms of dementia ; 4. Functional neuroproteomics ;
5. Neuroblastoma and stem cell therapy ; 6. Hematopoietic stem cell treatment for epilepsy  and 7. Experimental rodent
models of vascular dementia .
Last but not the least, GEs are also thankful to the Editor-in-Chief (Prof. Edoardo Spina) and the management of CNS &
Neurological Disorders - Drug Targets for their cooperation throughout the processing of the manuscripts.
This issue of CNS & Neurological Disorders - Drug Targets contains a series of articles that cover the major mechanisms
of nerve injury and potential therapeutic strategies. Nerve injury mainly manifests as metabolic stress, ion disorder, biochemical,
molecular and biological cascade events, eventually leading to neuronal death. Cell death is divided into two categories,
Accidental Cell Death (ACD) and Regulated Cell Death (RCD); RCD includes apoptosis, necroptosis, autophagy, pyroptosis,
and ferroptosis, etc. . In the central nervous system, apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis are the
main form of neuronal death [2, 3], which have become a potential therapeutic target for the nervous system disease .
Glaucoma, Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), cerebral Ischemia Injury (CII), and delirium are clinical
neurological diseases, resulting from a complex series of pathophysiological events, including oxidative, excitotoxicity, inflammation,
and nitrative stress; such events induce neuronal death. Due to the limited understanding of their pathological
mechanism, the outcomes of current clinical therapeutic approaches are not able to satisfy the need to treat these diseases.
Glaucoma is a multifactorial optic neuropathy progressively characterized by structural loss of Retinal Ganglion Cells (RGCs)
and irreversible loss of vision, and acute High Intraocular Pressure (aHIOP) injury-induced losses of RGCs have been explored,
such as apoptosis, autophagy, and necrosis [5, 6]. Yu et al. revealed that pyroptosis plays a vital role in retinal neuronal death,
especially in the ganglion cell layer, by acute HIOP injury that occurs at the 6th hour after HIOP injury. Furthermore, melatonin
prevents retinal neurons of pyroptosis via NF-κB/NLRP3 axis after HIOP injury in rats . SCI is a severe condition usually
accompanied by an inflammatory process that gives rise to uncontrolled local apoptosis and a subsequent unfavorable prognosis,
and one reason for this unfavorable outcome could be the activation of the NLRP3 inflammasome . He et al. demonstrated
that MCC950 exerts neuroprotective effects by reducing neuronal apoptosis, preserving the survival of the remaining neurons,
attenuating the severity of the damage, and promoting the recovery of motor function after SCI . Perampanel is a highly
selective and non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) antagonist,
which has been licensed as an orally administered antiepileptic drug in more than 55 countries . Chen et al. found that perampanel
significantly suppresses necroptosis after in vitro TBI model of primary cultured cortical neurons, as well as morphological
change and inhibition of Lactate Dehydrogenase (LDH) release and caspase-3 activation . Spastin participates in the
growth and regeneration of neurites by severing microtubules into small segments. Li et al. showed that spastin interacts with
CRMP2 to regulate neurite outgrowth and branch formation by controlling microtubule dynamics through phosphorylation
modifications , revealing the underlying microtubule mechanism of neurites outgrowth during neuronal development and
also proposing a feasible intervention pathway for reconstructing neural network connections after nerve injury.
Research on Post-Traumatic Stress Disorder (PTSD) is of great interest, especially now in the face of the global spread of
COVID-19. The Long Interspersed Element-1 (LIE-1) participates in memory formation, and DNA methylation patterns of
LIE-1 may suggest resilience or vulnerability factors for PTSD, of which the principal manifestation is a pathological exacerbation
of fear memory . Zhang et al. demonstrated that the retrotransposition of LIE-1 participates in the reconsolidation of
fear memory after the reactivation of fear memory. With lamivudine treatment, spontaneous recovery decreases with time after
recent and remote fear memory recall, providing clues for understanding the roles of LIE-1 in fear memory .
There are also three reviews that give our readers some insights and reflections. TBI is still the worldwide leading cause of
mortality and morbidity in young adults. Recent insights into the TBI pathophysiology have established microglial activation as
a hallmark of all types of TBI . The inflammatory response to injury is necessary and beneficial, while the death of activated
microglial is not. Nathalie et al. present new insights on the therapeutic and maladaptive features of the immune response
after TBI with emphasis on microglial polarization, such as low-frequency electrical stimulation, IL-1R antagonism, Anakinra,
anti-CD47, CSFR1 and NLRP inhibitors . This review presents a guide for TBI inflammation towards neural repair and
regeneration rather than secondary injury and degeneration by mitigating neuroinflammation via modulation of microglial response.
In East Asia, Chinese herbal medicines have been known for centuries to protect and improve the nervous system,
which have emerged as new pharmaceuticals for the treatment of ischemic neuronal injury via targeting the differently regulated
cell death pathways. Wu et al. reviewed that Chinese Herbal Medicine can target death receptor-mediated and mitochondrial
pathways to regulate apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. . Notably, many herbs have been
shown to target multiple mechanisms of regulated neuronal death and, in combination, may exert synergistic effects on signaling
pathways, thereby attenuating multiple aspects of ischemic pathology. Statins, as inhibitors of 3-Hydroxy-3-Methylglutaryl
Coenzyme A (HMG-CoA) reductase, have been identified as potential medications for the treatment of delirium because they
can significantly reduce the incidence of delirium . Chen et al. reviewed that Statins can alleviate delirium via reducing
neuroinflammation, neurotransmitters, cerebral hypoperfusion, and microthrombosis, which may highlight the clinical application
potential of statins in the therapy of delirium. However, the clinical effects of statins still provoke debate . Thus, a
larger sample size and better designed randomized trials are needed in the future, and appropriate drug or patient choice is also
Due to the different academic backgrounds of the researchers, each of the above studies can be regarded as an independent
research area. However, these studies can be put together as a whole to provide a strong indication of the effect of drug intervention on a particular neurological disorder. Therefore, given the trend and urgency in this area, we believe that this topic will
attract the attention of researchers in relevant fields, including drug developers, neurobiologists and clinical neurologists. This
special issue will also provide some advanced insights into the development of the field, in particular the research related to
neural regeneration and functional recovery.
This issue is devoted to promote the publication of original findings and provide novel insights. Here, we have articles with
scientific findings, as well as reviews, submitted by investigators at renowned medical and research institutions worldwide.
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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