Association Between the Endocannabinoid System-Related Gene Variants and Epilepsy.

The endocannabinoid system (ECS) is an intricate network consisting of receptors, enzymes, and endogenous ligands that play a pivotal role in various neurological processes. It has been implicated in the pathophysiology of several neurological disorders, including epilepsy. Extensive research has demonstrated the involvement of genetic factors in influencing the susceptibility to and progression of epilepsy. In this study, we focused on investigating the connection between genetic variations in genes related to the ECS and the occurrence of epilepsy. Some ECS-related gene variants were selected and genotyping was performed using the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. Interestingly, CNR1 rs12720071 genotype (OR 16.33, 95% CI 1.8-149; p = 0.001) showed an association with generalized epilepsy and MGLL rs604300 genotype (OR 2, 95% CI 1.1-3.4; p = 0.013) demonstrated a relationship with females diagnosed with focal epilepsy. So, studying CNR1, MGLL, and their genetic variations provides insights into the role of the endocannabinoid system in health and diseases. Moreover, they hold the potential to pave the way for the development of novel therapeutic approaches specifically targeting them.

Biosensors, Recent Advances in Determination of BDNF and NfL.

Key biomarkers such as Brain Derived Neurotrophic Factor (BDNF) and Neurofilament light chain (NfL) play important roles in the development and progression of many neurological diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In these clinical conditions, the underlying biomarker processes are markedly heterogeneous. In this context, robust biomarker discovery is of critical importance for screening, early detection, and monitoring of neurological diseases. The difficulty of directly identifying biochemical processes in the central nervous system (CNS) is challenging. In recent years, biomarkers of CNS inflammatory response have been identified in various body fluids such as blood, cerebrospinal fluid, and tears. Furthermore, biotechnology and nanotechnology have facilitated the development of biosensor platforms capable of real-time detection of multiple biomarkers in clinically relevant samples. Biosensing technology is approaching maturity and will be deployed in communities, at which point screening programs and personalized medicine will become a reality. In this multidisciplinary review, our goal is to highlight clinical and current technological advances in the development of multiplex-based solutions for effective diagnosis and monitoring of neuroinflammatory and neurodegenerative diseases. The trend in the detection if BDNF and NfL.

The study of rs324420 (C385A) polymorphism of the FAAH gene of the endocannabinoid system in patients with epilepsy and ADHD.

The endocannabinoid (eCB) system regulates many physiological functions in the central nervous system. Fatty acid amide hydrolase (FAAH) is an essential enzyme in the eCB system, degrading anandamide. Single nucleotide polymorphism (SNP) rs324420 is a common genetic polymorphism of the FAAH gene and has been associated with susceptibility to neurological conditions. This study examined whether the SNP rs324420 (C385A) is associated with epilepsy and attention deficit hyperactivity disorder (ADHD). This study consists of two case-control parts. The first part comprises 250 epilepsy subjects and 250 healthy individuals as controls. The second one comprises 157 cases with ADHD and 136 healthy individuals as controls. Genotyping was carried out using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. Interestingly, the FAAH C384A genotype (OR 1.755, 95 % CI 1.124-2.742, p = 0.013) and allele (OR 1.462, 95 % CI 1.006-2.124, p = 0.046) distribution showed an association with generalized epilepsy. On the other hand, this SNP was not associated with the risk of ADHD. To our knowledge, there was no study on the association between rs324420 (C385A) polymorphism and the risks of ADHD or epilepsy. This study provided the first evidence of an association between generalized epilepsy and rs324420 (C385A) of FAAH. Larger sample sizes and functional studies are warranted to explore the clinical utility of FAAH genotyping as a possible marker for increased generalized epilepsy risk.

Fatty acid amide hydrolase C385A polymorphism affects susceptibility to various diseases.

The endocannabinoid (eCB) system is an important neuromodulatory system with its extensive network of receptors throughout the human body that has complex actions in the nervous system, immune system, and all of the body's other organs. Fatty acid amide hydrolase (FAAH) is an important membrane-bound homodimeric degrading enzyme that controls the biological activity of N-arachidonoylethanolamide (AEA) in the eCB system and other relevant bioactive lipids. It has been shown that several single nucleotide polymorphisms (SNPs) of FAAH are associated with various phenotypes and diseases including cardiovascular, endocrine, drug abuse, and neuropsychiatric disorders. A common functional and most studied polymorphism of this gene is C385A (rs324420), which results in the replacement of a conserved proline to threonine in the FAAH enzyme structure, leads to a reduction of the activity and expression of FAAH, compromises the inactivation of AEA and causes higher synaptic concentrations of AEA that can be associated with several various phenotypes. The focus of this review is on evidence-based studies on the associations of the FAAH C385A polymorphism and the various diseases or traits. Although there was variability in the results of these reports, the overall consensus is that the FAAH C385A genotype can affect susceptibility to some multifactorial disorders and can be considered a potential therapeutic target.

Sensitive electrochemical recognition of α-synuclein protein in human plasma samples using bioconjugated gold nanoparticles: An innovative immuno-platform to assist in the early stage identification of Parkinson's disease by biosensor technology.

This research work explains the development of an electrochemical immunosensor for the selective recognition of SNCA in human biofluids. An innovative protocol was proposed for the green synthesis of gold nanoparticle-supported dimethylglyoxime (AuNPs@DMGO) using one-step electrogeneration method. Also, the application of AuNPs@DMGO for the sensitive quantification of α-Synuclein (SNCA) protein and its biomedical analysis. So, an innovative sandwich immunosensor was designed for the sensitive identification of SNCA antigen in an aqueous solution. The gold nanoparticles (AuNPs) were decorated on the surface of the glassy carbon electrode by chronoamperometry technique to provide appropriate immobilization surface with a large number of active sites for immobilization of specific biotinylated antibody (Ab1) and against SNCA protein. Then, the sandwich-type immuno-platform was completed by the attachment of secondary antibody (HRP conjugated Ab [Ab2]) to the primary complexes on the surface of the electrode. For the first time, α-Synuclein protein was measured with an acceptable linear range of 4-64 ng/mL and a lower limit of quantification of 4 ng/mL. Benefiting from the simplicity and high sensitivity, the proposed method shows a potential of employment in clinical applications and high-throughput screening of Parkinson's disease using POC.

Correction: Bioconjugation of 2-arachidonoyl glycerol (2-AG) biotinylated antibody with gold nano-flowers toward immunosensing of 2-AG in human plasma samples: a novel immuno-platform for the screening of immunomodulation and neuroprotection using biosensing.

Correction for 'Bioconjugation of 2-arachidonoyl glycerol (2-AG) biotinylated antibody with gold nano-flowers toward immunosensing of 2-AG in human plasma samples: a novel immuno-platform for the screening of immunomodulation and neuroprotection using biosensing' by Ahmad Mobed et al., Anal. Methods, 2021, 13, 311-321, https://doi.org/10.1039/D0AY02135K.

Biosensors technology for anti-epileptic drugs.

A broad group of antiepileptic drugs (AEDs) often controls the frequency of seizures. Given the variability of pharmacokinetics, narrow target range, and the difficulty of identifying signs of toxicity from laboratory responses, therapeutic monitoring of AEDs plays a vital role in optimizing drug administration. Nanomaterials, especially biosensor-based methods, can facilitate the analysis of these agents with unique advantages such as rapid analysis, sensitivity, selectivity, and low cost. This review describes recent advances in biosensors developed to analyze AEDs. First, we described common electrochemical measurement techniques and types of deposited electrode substrates. Additionally, various chemical and biological modifiers to improve the sensitivity and selectivity of the sensor have been categorized and briefly described. Finally, the prospects for developing an electrochemical platform for quantifying AEDs are presented.

An innovative electrochemical immuno-platform towards ultra-sensitive monitoring of 2-arachidonoyl glycerol in samples from rats with sleep deprivation: bioanalysis of endogenous cannabinoids using biosensor technology.

The endocannabinoid system (ECS) is a complex of neurotransmitters in the central nervous system and plays a key role in regulating cognitive and physiological processes. 2-Arachidonoylglycerol (2-AG) is one of the imperative endocannabinoids that play key roles in the central nervous system. It acts as a signaling lipid and activates the cannabinoid CB1 receptor. In addition, 2-AG is involved in a variety of physiological functions such as energy balance, emotion, pain sensation, cognition, and neuroinflammation. So, rapid and specific diagnosis of 2-AG is of great importance in medical neuroscience. The development of new methods in this area has been one of the most important research areas in recent years. Herein, an innovative immunosensor is developed for quantification of 2-AG. For this means, gold nanostars (GNS) were synthesized and conjugated with a specific biotinylated antibody against 2-AG. The resultant bioconjugate, a bioreceptor with GNS, was immobilized on the surface of a gold electrode and used for the detection of the antigen based on the immunocomplex formation followed by analysis using different electrochemical techniques. For the first time, 2-AG protein was measured with an excellent linear range of 0.48-1 ng mL-1 and lower limit of quantification of 0.48 ng L-1 by the electroanalysis method. The engineered immunosensor showed high sensitivity and specificity in the presence of interfering antigens, proving its utility in neurological disorder detection. This immunosensor is the first sandwich type immunoassay for the detection of 2-AG in real samples and the first innovation of designing a novel sandwich type immunosensor for this analyte. Also, excellent analytical results are other advantages of this biosensor for the detection of 2-AG in human plasma samples and serum samples of rats under sleep deprivation. So, this is the first report of an immunosensor of 2-AG using a sandwich type immunosensor.

Rapid treatments for depression: Endocannabinoid system as a therapeutic target.

Current first-line treatments for major depressive disorder (MDD), i.e., antidepressant drugs and psychotherapy, show delayed onset of therapeutic effect as late as 2-3 weeks or more. In the clinic, the speed of beginning of the actions of antidepressant drugs or other interventions is vital for many reasons. Late-onset means that depression, its related disability, and the potential danger of suicide remain a threat for some patients. There are some rapid-acting antidepressant interventions, such as sleep deprivation, ketamine, acute exercise, which induce a significant response, ranging from a few hours to maximally one week, and most of them share a common characteristic that is the activation of the endocannabinoid (eCB) system. Activation of this system, i.e., augmentation of eCB signaling, appears to have anti-depressant-like actions. This article puts the idea forward that the activation of eCB signaling represents a critical mechanism of rapid-acting therapeutic interventions in MDD, and this system might contribute to the development of novel rapid-acting treatments for MDD.

Biosensors in Parkinson's disease.

Parkinson's disease (PD) is one of the most critical disorders of the elderly and strongly associated with increased disability, and reduced quality of life. PD is a progressive neurodegenerative disease affecting more than six million people worldwide. Evaluation of clinical manifestations, as well as movement disorders by a neurologist and some routine laboratory tests are the most important diagnostic methods for PD. However, routine and old methods have several disadvantages and limitations such as low sensitivity and selectivity, high cost, and need for advanced equipment. Biosensors technology opens up new diagnoses approach for PD with the use of a new platform that allows reliable, repeatable, and multidimensional identification to be made with minimal problem and discomfort for patients. For instance, biosensing systems can provide promising tools for PD treatment and monitoring. Amongst biosensor technology, electrochemical techniques have been at the frontline of this progress, thanks to the developments in material science, such as gold nanoparticles (AuNPs), quantum dots (QDs), and carbon nanotubes (CNTs). This paper evaluates the latest progress in electrochemical and optical biosensors for PD diagnosis.

Bioconjugation of 2-arachidonoyl glycerol (2-AG) biotinylated antibody with gold nano-flowers toward immunosensing of 2-AG in human plasma samples: A novel immuno-platform for the screening of immunomodulation and neuroprotection using biosensing.

Human 2-arachidonoylglycerol (2-AG) is an agonist of endocannabinoid system and acts as an important modulator of many physiological processes such as emotional state and pain sensation. Identification and quantification of 2-AG is vital for medical and pathological processes. There are no reports on the measurement of 2-AG in human biofluids using modern methods such as biosensors. This study reports an ultra-sensitive and selective immunosensor to determine endocannabinoids 2-AG in human plasma samples. In this study, gold nano-flowers (AuNFs) were synthesized and conjugated with a specific biotinylated antibody of 2-AG. Bioconjugated composite (bioreceptor with AuNFs) was immobilized on the surface of a gold electrode and used for the monitoring of the antigen (target molecules) based on the immunoreaction process. Moreover, a constructed interface was characterized by field-emission scanning electron microscopy (FE-SEM), dynamic light scattering (DLS), transmission electron microscopy (TEM) and zeta potential methods. Using the proposed immuno-platform, 2-AG was determined in two dynamic ranges of 0.00024-0.0078 ng L-1 and 2-16 ng L-1 with a lower limit of quantitation (LLOQ) of 0.00024 ng L-1. These results suggest that our immunosensor might be appropriate for an early diagnosis of 2-AG towards the screening of immunomodulatory activity and neuroprotection.

The impact of sleep deprivation on sexual behaviors and FAAH expression in the prefrontal cortex of male rats.

Sleep deprivation (SD) causes alterations in the function of the endocannabinoid (EC) system and also results in alteration in many behaviors such as increased anxiety, deteriorated alertness, memory deficits, as well as sexual behaviors. Controversial data about the effects of SD on sexual response are provided. Fatty acid amide hydrolase (FAAH), the enzymes involved in the degradation of the EC system play an important role in the function of the EC system. This study aimed to investigate the effect of REM SD (RSD) and total SD (TSD) on the sexual behaviors and FAAH expression in the prefrontal cortex (PFC) of male rats. RSD was carried out through the flower pot technique for 24 h and 48 h, and TSD also was induced by keeping awake the rats by gentle handling for 6 h. Immediately after RSD and TSD, sexual behaviors were recorded for 45 min. Sexual behaviors were reduced by both types of RSD and TSD. The deleterious effects of 24 h RSD were more severe compared with 6 h of TSD. Serum testosterone concentration was significantly higher after TSD but not RSD compared to the normal sleep (NS) group. FAAH expression in the PFC was significantly reduced after both RSD and TSD compared to the NS group. Given that the function of the EC system has been previously shown to change different behaviors such as sexual activity, our results could suggest that behavioral effects of both types of SD on sexual behavior may partially result from activation of this signaling pathway by the reduction of FAAH in the PFC.

Corticosterone impairs contextual fear recall after reactivation in the ovariectomized rat model of menopause.

Menopause affects most physiological processes, including cognitive functions, although, the extent to which these functions are affected is not clear. The aim of this study was to investigate the effect of corticosterone (CORT) administration after reactivation on contextual fear recall in ovariectomized female rats. Adult female rats were ovariectomized and trained in a fear conditioning chamber (conditioned stimulus, CS) using electrical foot shock (unconditioned stimulus, US); with moderate or strong intensities. After reactivation 48 h later, rats were injected with CORT (0.3, 3 or 10 mg/kg) or vehicle. 2, 4 and 11 days after memory reactivation freezing behavior was scored. The results showed that CORT at the low dose of 0.3 mg/kg when injected after memory reactivation impaired memory recall in both moderate and strong shock on the third test (day 11). Because extinction process occurs after repeated presentation of CS without US (electrical shock during reactivation and recall days), memory impairment in our experiments is more likely to be due to increased memory extinction. Our findings suggest that CORT administration after reactivation of fear memory impairs recall in the rat model of menopause and more research is needed to find the exact mechanisms involved in this process which is of great value for treating cognitive problems during menopause.

Impacts of epidural electrical stimulation on Wnt signaling, FAAH, and BDNF following thoracic spinal cord injury in rat.

Electrical stimulation (ES) has been shown to improve some of impairments after spinal cord injury (SCI), but the underlying mechanisms remain unclear. The Wnt signaling pathways and the endocannabinoid system appear to be modulated in response to SCI. This study aimed to investigate the effect of ES therapy on the activity of canonical/noncanonical Wnt signaling pathways, brain-derived neurotrophic factor (BDNF), and fatty-acid amide hydrolase (FAAH), which regulate endocannabinoids levels. Forty male Wistar rats were randomly divided into four groups: (a) Sham, (b) laminectomy + epidural subthreshold ES, (c) SCI, and (d) SCI + epidural subthreshold ES. A moderate contusion SCI was performed at the thoracic level (T10). Epidural subthreshold ES was delivered to upper the level of T10 segment every day (1 hr/rat) for 2 weeks. Then, animals were killed and immunoblotting was used to assess spinal cord parameters. Results revealed that ES intervention for 14 days could significantly increase wingless-type3 (Wnt3), Wnt7, ß-catenin, Nestin, and cyclin D1 levels, as well as phosphorylation of glycogen synthase kinase 3ß and Jun N-terminal kinase. Additionally, SCI reduced BDNF and FAAH levels, and ES increased BDNF and FAAH levels in the injury site. We propose that ES therapy may improve some of impairments after SCI through Wnt signaling pathways. Outcomes also suggest that BDNF and FAAH are important players in the beneficial impacts of ES therapy. However, the precise mechanism of BDNF, FAAH, and Wnt signaling pathways on SCI requires further investigation.

Bioassay: A novel approach in antipsychotic pharmacology.

Accurate identification and measurement of antipsychotic drugs in in-vivo and in-vitro environment has a key role in the development and design of drugs, as any slight change in their dosage can affect the treatment process. Determination of antipsychotics in physiological fluids such as blood, plasma and urine are important in drug tablets and medical approaches. Chromatography is the main method used in the determination of antipsychotic drugs but this technique, despite its relative sensitivity, is a costly and complicated method. Biosensors, as simple, low-cost and highly sensitive and specific tools, can be the best alternative to eliminate the drawbacks of routine methods. For this purpose, various biosensors have been extensively developed in the recent years. The main objective of the present study is to introduce and collect recently developed biosensors for the measurement and detection of antipsychotic drugs. Therapeutic drug monitoring (TDM) is a fundamental principle in pharmaceuticals, with the primary goal being to reduce and eliminate the side effects of drugs. This study shows that biosensors can be a modern and novel approach in the field of TDM.

A Place-based Assessment of Flash Flood Hazard and Vulnerability in the Contiguous United States.

Flash flood is among the most catastrophic natural hazards which causes disruption in the environment and societies. Flash flood is mainly initiated by intense rainfall, and due to its rapid onset (within six hours of rainfall), taking action for effective response is challenging. Building resilience to flash floods require understanding of the socio-economic characteristics of the societies and their vulnerability to these extreme events. This study provides a comprehensive assessment of socio-economic vulnerability to flash floods and investigates the main characteristics of flash flood hazard, i.e. frequency, duration, severity, and magnitude. A socio-economic vulnerability index is developed at the county level across the Contiguous United States (CONUS). For this purpose, an ensemble of social and economic variables from the US Census and the Bureau of Economic Analysis were analyzed. Then, the coincidence of socio-economic vulnerability and flash flood hazard were investigated to identify the critical and non-critical regions. Results show that the southwest U.S. experienced severe flash flooding with high magnitude, whereas the Northern Great Plains experience lower severity and frequency. Critical counties (high-vulnerable-hotspot) are mostly located in the southern and southwestern parts of the U.S. The majority of counties in the Northern Great Plains indicate a non-critical status.

The first evidence of an association between a polymorphism in the endocannabinoid-degrading enzyme FAAH (FAAH rs2295633) with attention deficit hyperactivity disorder.

Several single nucleotide polymorphisms (SNPs) of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoids, have been shown to be associated with many neuropsychiatric disorders. Here, FAAH rs2295633 was studied in ADHD and case-control healthy children. There was a significant difference in the allele frequency (P = .04) and genotype distribution (P = .04) of the FAAH rs2295633 between ADHD cases and controls. The ADHD children appeared to have less of TT genotype (OR 0.396, 95% CI 0.178-0.884, p = .024) and T allele (OR 0.658, 95% CI 0.440-0.982, p = .04). To our best knowledge, this is the first statistical significant association between FAAH rs2295633 genotype and ADHD disorder. Larger sample sizes and functional studies are warranted to explore the clinical utility of FAAH genotyping as a possible marker for increased ADHD risk in children.

Future drought risk in Africa: Integrating vulnerability, climate change, and population growth.

Drought risk refers to the potential losses from hazard imposed by a drought event, and it is generally characterized as a function of vulnerability, hazard, and exposure. In this study, drought risk is assessed at a national level across Africa, and the impacts of climate change, population growth, and socioeconomic vulnerabilities on drought risk are investigated. A rigorous framework is implemented to quantify drought vulnerability considering various sectors including economy, energy and infrastructure, health, land use, society, and water resources. Multi-model and multi-scenario analyses are employed to quantify drought hazard using an ensemble of 10 regional climate models and a multi-scalar drought index. Drought risk is then assessed in each country for 2 climate emission pathways (RCP4.5 and RCP8.5), 3 population scenarios, and 3 vulnerability scenarios during three future periods between 2010 and 2100. Drought risk ratio is quantified, and the role of each component (i.e. hazard, vulnerability, and exposure) is identified, and the associated uncertainties are also characterized. Results show that drought risk is expected to increase in future across Africa with varied rates for different models and scenarios. Although northern African countries indicate aggravating drought hazard, drought risk ratio is found to be highest in central African countries as a consequent of vulnerability and population rise in that region. Results indicate that if no climate change adaptation is implemented, unprecedented drought hazard and risk will occur decades earlier. In addition, controlling population growth is found to be imperative for mitigating drought risk in Africa (even more effective than climate change mitigation), as it improves socioeconomic vulnerability and reduces potential exposure to drought.

Hydrological drought persistence and recovery over the CONUS: A multi-stage framework considering water quantity and quality.

Hydrological droughts have considerable negative impacts on water quantity and quality, and understanding their regional characteristics is of crucial importance. This study presents a multi-stage framework to detect and characterize hydrological droughts considering both streamflow and water quality changes. Hydrological droughts are categorized into three stages of growth, persistence, retreat, and water quality variables (i.e., water temperature, dissolved oxygen concentration, and turbidity) are utilized to further investigate drought recovery. The framework is applied to 400 streamflow gauges across the Contiguous United States (CONUS) over the study period of 1950-2016. The method is illustrated for the 2012 US drought, which affected most of the nation. Results reveal the duration, frequency, and severity of historical droughts in various regions as well as their spatial consistencies and heterogeneities. Furthermore, duration of each stage of drought (i.e., growth, persistence, and retreat) is also assessed and the spatial patterns are diagnosed across the CONUS. Considering the water quality variables, increased water temperature (4 °C on average) and reduced dissolved oxygen concentration (2.5 mg/L on average) were observed during drought episodes, both of which impose severe consequences on ecology of natural habitats. On the contrary, turbidity was found to decrease during droughts, and indicate a sudden increase when drought terminates, due to increase in runoff. Varied drought recovery durations are perceived for different water quality variables, and in general, it takes about two more months for water quality variables to recover from a drought, following the hydrological drought termination.

Multi-dimensional assessment of drought vulnerability in Africa: 1960-2100.

Drought vulnerability is a complex concept that identifies the capacity to cope with drought, and reveals the susceptibility of a system to the adverse impacts of drought. In this study, a multi-dimensional modeling framework is carried out to investigate drought vulnerability at a national level across the African continent. Data from 28 factors in six different components (i.e. economy, energy and infrastructure, health, land use, society, and water resources) are collected for 46 African countries during 1960-2015, and a composite Drought Vulnerability Index (DVI) is calculated for each country. Various analyses are conducted to assess the reliability and accuracy of the proposed DVI, and the index is evaluated against historical observed drought impacts. Then, regression models are fitted to the historical time-series of DVI for each country, and the models are extrapolated for the period of 2020-2100 to provide three future scenarios of DVI projection (low, medium, and high) based on historical variations and trends. Results show that Egypt, Tunisia, and Algeria are the least drought vulnerable countries, and Chad, Niger, and Malawi are the most drought vulnerable countries in Africa. Future DVI projections indicate that the difference between low- and high-vulnerable countries will increase in future, with most of the southern and northern African countries becoming less vulnerable to drought, whereas the majority of central African countries indicate increasing drought vulnerability. The projected DVIs can be utilized for long-term drought risk analysis as well as strategic adaptation planning purposes.