Neurotransmitter systems in the etiology of major neurological disorders: Emerging insights and therapeutic implications.

Neurotransmitters serve as chemical messengers playing a crucial role in information processing throughout the nervous system, and are essential for healthy physiological and behavioural functions in the body. Neurotransmitter systems are classified as cholinergic, glutamatergic, GABAergic, dopaminergic, serotonergic, histaminergic, or aminergic systems, depending on the type of neurotransmitter secreted by the neuron, allowing effector organs to carry out specific functions by sending nerve impulses. Dysregulation of a neurotransmitter system is typically linked to a specific neurological disorder. However, more recent research points to a distinct pathogenic role for each neurotransmitter system in more than one neurological disorder of the central nervous system. In this context, the review provides recently updated information on each neurotransmitter system, including the pathways involved in their biochemical synthesis and regulation, their physiological functions, pathogenic roles in diseases, current diagnostics, new therapeutic targets, and the currently used drugs for associated neurological disorders. Finally, a brief overview of the recent developments in neurotransmitter-based therapeutics for selected neurological disorders is offered, followed by future perspectives in that area of research.

New Alzheimer Disease Drugs, Long COVID and the Central Nervous System, and a Nasal Spray for Migraines-Highlights From the 2023 American Academy of Neurology Conference.

This Medical News article discusses research presented at the recent American Academy of Neurology Conference.

Brain borders at the central stage of neuroimmunology.

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Restoration Algorithm-Based Ultrasound Image in Evaluating the Effect of Dexmedetomidine on Patients with Neurological Disorder Anesthetized by Sevoflurane.

The study focused on the application value of ultrasound images processed by restoration algorithm in evaluating the effect of dexmedetomidine in preventing neurological disorder in patients undergoing sevoflurane anesthesia. 90 patients undergoing tonsillectomy anesthesia were randomly divided into normal saline group, propofol group, and dexmedetomidine group. The ultrasound images were processed by restoration algorithm, and during the postoperative recovery period, ultrasound images were used to evaluate. The results showed that the original ultrasonic image was fuzzy and contained interference noise, and that the image optimized by restoration algorithm was clear, without excess noise, and the image quality was significantly improved. In the dexmedetomidine group, the extubation time was 10.6 ± 2.3 minutes, the recovery time was 8.4 ± 2.2 minutes, the average pain score during the recovery period was 2.6 ± 0.7, and the average agitation score was 7.2 ± 2.4. Of 30 patients, there were 13 cases with vertigo and 1 case with nausea and vomiting. The vascular ultrasound imaging showed that, in the dexmedetomidine group, the peak systolic velocities (PSV) of the bilateral vertebral arteries during the recovery period were 67.7 ± 14.3 and 67.9 ± 15.2 cm/s, respectively; the end-diastolic velocities (EDV) of the bilateral vertebral arteries were 27.8 ± 6.7 and 24.69 ± 5.9 cm/s, respectively; the PSV in bilateral internal carotid artery systolic peak velocities were 67.2 ± 13.9 and 67.8 ± 12.7 cm/s, respectively; the EDV in bilateral internal carotid arteries were 27.7 ± 5.3 and 26.9 ± 4.9 cm/s, respectively; bilateral vertebral artery resistance indexes (RIs) were 0.6 ± 0.02 and 0.71 ± 0.08, respectively; the bilateral internal carotid artery RIs were 0.57 ± 0.04 and 0.58 ± 0.06, respectively, all better than the normal saline group (12.1 ± 2.5 minutes, 10.1 ± 2.3 minutes, 3.9 ± 0.6, 10.6 ± 3.7, 15 cases, 11 cases, 81.5 ± 13.6, 80.7 ± 11.6 cm/s, 29.3 ± 6.8, 28.9 ± 6.7 cm/s, 74.3 ± 10.2, 73.9 ± 12.5 cm/s, 29.1 ± 4.3, 29 ± 4.5 cm/s, 0.84 ± 0.06, 0.83 ± 0.05, 0.8 ± 0.04, and 0.81 ± 0.05) and the propofol group (11.4 ± 2.1 minutes, 9.0 ± 2.1 minutes, 3.4 ± 0.8, 8.5 ± 2.3, 12 cases, 9 cases, 72.5 ± 12.9, 73.4 ± 11.8 cm/s, 28.6 ± 5.4, 26.5 ± 5.1 cm/s, 72.1 ± 11.4, 73.5 ± 10.6 cm/s, 28.8 ± 5.6, 27.3 ± 4.7 cm/s, 0.78 ± 0.07, 0.82 ± 0.06, 0.76 ± 0.03, and 0.78 ± 0.05), and the differences were statistically significant (P < 0.05). In conclusion, ultrasound images processed by restoration algorithm have high image quality and high resolution. The dexmedetomidine can prevent neurological disorder in patients with sevoflurane anesthesia and is suggested in postoperative rehabilitation.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

The threat of programmed DNA damage to neuronal genome integrity and plasticity.

The neuronal genome is particularly sensitive to loss or attenuation of DNA repair, and many neurological diseases ensue when DNA repair is impaired. It is well-established that the neuronal genome is subjected to stochastic DNA damage, most likely because of extensive oxidative stress in the brain. However, recent studies have identified unexpected high levels of 'programmed' DNA breakage in neurons, which we propose arise during physiological DNA metabolic processes intrinsic to neuronal development, differentiation and maintenance. The role of programmed DNA breaks in normal neuronal physiology and disease remains relatively unexplored thus far. However, bulk and single-cell sequencing analyses of neurodegenerative diseases have revealed age-related somatic mutational signatures that are enriched in regulatory regions of the genome. Here, we explore a paradigm of DNA repair in neurons, in which the genome is safeguarded from erroneous impacts of programmed genome breakage intrinsic to normal neuronal function.

Lipopolysaccharide induced altered signaling pathways in various neurological disorders.

Neuroinflammation is defined as an inflammatory response within the brain or spinal cord, whereas the brain's innate immune system is triggered by various inflammatory challenges such as injury, infection, exposure to toxin (LPS) and ageing, which result in cognitive impairment and neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Lipopolysaccharide (LPS) is a main structural component of the outer membrane of gram-negative bacteria, widely used systematically to stimulate the immune system and to generate profound physiological and behavioural changes. It consists of three parts: lipid A, a core oligosaccharide and an O side chain. It is reported by several scientists that, besides the systemic alteration, LPS also induces neurodegeneration by promoting neuroinflammation upon binding with the stimulation of Toll-like receptor-4 (TLR4) receptors present on glial cells. The mammalian Toll-like receptor (TLR) family consists of 13 membranes and TLR was discovered as a crucial pattern recognition receptor (PPR) involved in the recognition of pathogen-associated molecular patterns (PAMPs). Future studies will show that damage/danger-associated molecular patterns (DAMPs) are recognised by the involvement of PPRs, generated by the host itself. The stimulation of TLR4 by lipopolysaccharide phosphorylates two signalling pathways, namely the MyD88-dependent pathway and the MyD88-independent pathway. This activation subsequently triggers the release of various pro-inflammatory cytokines that are necessary to activate innate immune responses, and then promotes neuroinflammation. In this review, we critically demonstrated the epidemiology of neuroinflammation, types of TLRs, the molecular mechanism of TLR4 and management of neuroinflammation.

2 Years into the Pandemic: What Did We Learn About the COVID-19 and Cerebellum?

Highly contagious pandemic due to novel coronavirus SARS-CoV-2, COVID-19 has significantly affected humankind. At the onset of the pandemic, it was believed that it primarily affects the respiratory and hematological system, and has minimal influence on the human brain, even less so on the cerebellum. It was thought that the effects of a pandemic on cerebellar disorders would be the same as it would affect any other chronic neurological disease. It turned out that our understanding of the effects of COVID-19 on the cerebellar system was premature. Over the last 2 years, we appreciated many diverse and direct effects of COVID-19 on cerebellar function. SARS-CoV-2 affects the cerebellum via direct viral invasion, but even more so through its effects on immune, hematological, and metabolic pathways. Increasing evidence suggested the indirect effects of COVID-19 on preexisting chronic cerebellar disease due to lack of in-person care and social isolation. This editorial concisely summarizes critical literature on COVID-19 and the cerebellum published over the last 2 years.

Nervous system consequences of COVID-19.

Neurological symptoms highlight the need to understand pathophysiologic mechanisms.

Acute Neurologic Dysfunction in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Acute neurologic dysfunction is common in critically ill children and contributes to outcomes and end of life decision-making. OBJECTIVE: To develop consensus criteria for neurologic dysfunction in critically ill children by evaluating the evidence supporting such criteria and their association with outcomes. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, by using a combination of medical subject heading terms and text words to define concepts of neurologic dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION: Studies were included if the researchers evaluated critically ill children with neurologic injury, evaluated the performance characteristics of assessment and scoring tools to screen for neurologic dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies with an adult population or premature infants (≤36 weeks' gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and studies not published in English with an inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from each study meeting inclusion criteria into a standard data extraction form by task force members. DATA SYNTHESIS: The systematic review supported the following criteria for neurologic dysfunction as any 1 of the following: (1) Glasgow Coma Scale score ≤8; (2) Glasgow Coma Scale motor score ≤4; (3) Cornell Assessment of Pediatric Delirium score ≥9; or (4) electroencephalography revealing attenuation, suppression, or electrographic seizures. CONCLUSIONS: We present consensus criteria for neurologic dysfunction in critically ill children.

Brain stimulation: a therapeutic approach for the treatment of neurological disorders.

Brain stimulation has become one of the most acceptable therapeutic approaches in recent years and a powerful tool in the remedy against neurological diseases. Brain stimulation is achieved through the application of electric currents using non-invasive as well as invasive techniques. Recent technological advancements have evolved into the development of precise devices with capacity to produce well-controlled and effective brain stimulation. Currently, most used non-invasive techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), whereas the most common invasive technique is deep brain stimulation (DBS). In last decade, application of these brain stimulation techniques has not only exploded but also expanded to wide variety of neurological disorders. Therefore, in the current review, we will provide an overview of the potential of both non-invasive (rTMS and tDCS) and invasive (DBS) brain stimulation techniques in the treatment of such brain diseases.

Metalloproteinases and their inhibitors in neurological disease.

Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological processes. We aim to review the MMP inhibition from a clinical perspective and its possible therapeutic use in the future. MMPs play a role in various neurodegenerative and cerebrovascular diseases such as large artery atherosclerosis and ischemic stroke; for example, MMPs increase blood-brain barrier permeability favoring neuroinflammation. Synthetic MMPs inhibitors have been tested mostly in oncological trials and failed to demonstrate efficacy; some of them were discontinued because of the severe adverse reactions. Tetracyclines, in submicrobial doses, act as an MMP inhibitor, although tetracyclines have not yet been proven effective in several neurological conditions in which they were tested against placebo; it is uncertain whether there may be a use for tetracyclines in cerebrovascular disease, as a neuroprotective agent or in dolichoectasia.

The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders.

Stress is a primary risk factor for several neuropsychiatric disorders. Evidence from preclinical models and clinical studies of depression have revealed an array of structural and functional maladaptive changes, whereby adverse environmental factors shape the brain. These changes, observed from the molecular and transcriptional levels through to large-scale brain networks, to the behaviours reveal a complex matrix of interrelated pathophysiological processes that differ between sexes, providing insight into the potential underpinnings of the sex bias of neuropsychiatric disorders. Although many preclinical studies use chronic stress protocols, long-term changes are also induced by acute exposure to traumatic stress, opening a path to identify determinants of resilient versus susceptible responses to both acute and chronic stress. Epigenetic regulation of gene expression has emerged as a key player underlying the persistent impact of stress on the brain. Indeed, histone modification, DNA methylation and microRNAs are closely involved in many aspects of the stress response and reveal the glutamate system as a key player. The success of ketamine has stimulated a whole line of research and development on drugs directly or indirectly targeting glutamate function. However, the challenge of translating the emerging understanding of stress pathophysiology into effective clinical treatments remains a major challenge.

Enhancing cardiac arrest survival with extracorporeal cardiopulmonary resuscitation: insights into the process of death.

Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging method of cardiopulmonary resuscitation to improve outcomes from cardiac arrest. This approach targets patients with out-of-hospital cardiac arrest previously unresponsive and refractory to standard treatment, combining approximately 1 h of standard CPR followed by venoarterial extracorporeal membrane oxygenation (VA-ECMO) and coronary artery revascularization. Despite its relatively new emergence for the treatment of cardiac arrest, the approach is grounded in a vast body of preclinical and clinical data that demonstrate significantly improved survival and neurological outcomes despite unprecedented, prolonged periods of CPR. In this review, we detail the principles behind VA-ECMO-facilitated resuscitation, contemporary clinical approaches with outcomes, and address the emerging new understanding of the process of death and capability for neurological recovery.

Neurological Soft Signs Are Associated With Altered White Matter in Patients With Schizophrenia.

Neurological soft signs (NSS) are related to grey matter and functional brain abnormalities in schizophrenia. Studies in healthy subjects suggest, that NSS are also linked to white matter. However, the association between NSS and white matter abnormalities in schizophrenia remains to be elucidated. The present study investigated, if NSS are related to white matter alterations in patients with schizophrenia. The total sample included 42 healthy controls and 41 patients with schizophrenia. We used the Neurological Evaluation Scale (NES), and we acquired diffusion weighted magnetic resonance imaging to assess white matter on a voxel-wise between subject statistic. In patients with schizophrenia, linear associations between NES with fractional anisotropy (FA), radial, axial, and mean diffusivity were analyzed with tract-based spatial statistics while controlling for age, medication dose, the severity of the disease, and motion. The main pattern of results in patients showed a positive association of NES with all diffusion measures except FA in important motor pathways: the corticospinal tract, internal capsule, superior longitudinal fascicle, thalamocortical radiations and corpus callosum. In addition, exploratory tractography analysis revealed an association of the right aslant with NES in patients. These results suggest that specific white matter alterations, that is, increased diffusivity might contribute to NSS in patients with schizophrenia.

Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies.

An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the heritability (h2SNP) of BCC, define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). h2SNP was calculated to be 49-61% depending on the estimated BCC prevalence. A total of 2407 SNPs across the genome accounted for nearly all the h2SNP of BCC, with an estimated 2003 SNPs of small effect, 349 SNPs of moderate effect, and 56 SNPs of large effect. Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h2SNP. We conclude that BCC is a moderately- to highly-heritable complex polygenetic disease resulting from contributions from hundreds to thousands of genetic variants with variable effect sizes. Understanding how much the BCC phenotype is determined by genetics and whether major gene mutations are likely to exist inform veterinarians and working/stock dog communities of the true nature of this condition.

Relationships between cardiovascular signs and neurological signs in asphyxiated neonates in Ilorin, North Central Nigeria.

BACKGROUND: Perinatal asphyxia is a condition associated with multiple organ dysfunctions inclusive of cardiovascular dysfunction. Neurologic predictors of survival have been studied, but little has been reported regarding cardiovascular signs and their role in determining outcome in asphyxia. OBJECTIVE: The study aimed to determine the relationship between cardiovascular signs and outcomes in asphyxiated newborns with hypoxic ischaemic encephalopathy. METHODS: This was a cross sectional study involving asphyxiated new-born babies recruited within the first 24 hours of life. Hypoxic ischaemic encephalopathy staging was done using Sarnat and Sarnat staging. All patients had a detailed cardiovascular examination on admission, after initial resuscitation (30 - 60 minutes) into admission, and were followed till final outcome: discharge or death. RESULTS: Eighty-five asphyxiated new-borns with HIE were studied over seven months. Abnormal cardiovascular-related signs identified in the patients included respiratory distress (64.7%), small volume pulse (57.6%), hypotension (52.9%), hypoxemia (48.2%) and shock (32.9%). Five babies died. None of the clinical signs had a significant relationship with mortality. CONCLUSION: Abnormal cardiovascular signs increased with the progression of HIE staging but had no relationship with mortality.