Exosomes as drug delivery vehicles and biomarkers for neurological and auditory systems.

Exosomes are small extracellular membrane particles that play a crucial role in intracellular signaling. Research shows that exosomes have the potential to be used as biomarkers or drug delivery systems in specific organs, such as the neurological system and the inner ear. Exosomes in neurological and auditory systems release different molecules when under stress versus in healthy states, highlighting their potential use as biomarkers in the identification of diseased states. Studies have suggested that exosomes can be harnessed for drug delivery to hard-to-reach organs, such as cochlear sensory hair cells and the brain due to their ability to cross the blood-labyrinth and blood-brain barriers. In this article, we describe the biogenesis, classification, and characterization methods of exosomes. We then discuss recent studies that indicate their potential usage as biomarkers and drug delivery systems to help treat inner ear and neurological disorders.

Beneficial Effects of Milk Having A2 ß-Casein Protein: Myth or Reality?

Diet has been shown to play an important role in maintaining normal homeostasis in the human body. Milk and milk products are a major component of the Western diet, but their consumption may predispose sensitive individuals to adverse health outcomes. Current literature about milk products recognizes various bioactive components including lactate, whey protein, and ß-casein protein. Specifically, cow milk has 2 major subvariants of its ß-casein protein, A1 and A2, due to a single nucleotide difference that changes the codon at position 67. Whereas the A2 polymorphism is unlikely to undergo enzymatic cleavage during digestion, the A1 polymorphism is more likely to undergo enzymatic cleavage resulting in the product peptide ß-casomorphin-7, a known µ-opioid receptor agonist. The objective of this article is to review the current understanding of the 2 major ß-casein subvariants and their effects on various organ systems that may have an impact on the health of an individual. Synthesis of the current existing literature on this topic is relevant given the increased association of milk consumption with adverse effects in susceptible individuals resulting in a rising interest in consuming milk alternatives. We discuss the influence of the ß-casein protein on the gastrointestinal system, endocrine system, nervous system, and cardiovascular system as well as its role in antioxidants and methylation. A1 milk consumption has been associated with enhanced inflammatory markers. It has also been reported to have an opioid-like response that can lead to manifestations of clinical symptoms of neurological disorders such as autism spectrum disorder. On the other hand, A2 milk consumption has been associated with beneficial effects and is easier to digest in sensitive individuals. Further research is warranted to investigate the short- and long-term effects of consumption of A1 ß-casein in comparison with milk with A2 ß-casein proteins.

Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications.

Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber-mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies.

Organ-on-chip models: Implications in drug discovery and clinical applications.

Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three-dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine-gut-stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ-on-chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ-on-chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine.

A perspective on stem cell therapy for ear disorders.

The use of stem cells in cell-based therapy is an emerging concept for the treatment of ear disorders. Tympanic membrane perforation (TMP) and inner ear disorders are some of the most commonly presented otologic disorders that can benefit from advances in cell-based therapy. Studies have already demonstrated that stem cell-based therapy can potentially be an effective treatment modality for acute and chronic TMP. Recent studies have also shown promise in application of cell-based approach to treat inner ear dysfunction. In this perspective, we will discuss the recent advancements regarding the use of cell-based therapy for ear disorders.

Indispensable Role of Ion Channels and Transporters in the Auditory System.

Ear is a complex system where appropriate ionic composition is essential for maintaining the tissue homeostasis and hearing function. Ion transporters and channels present in the auditory system plays a crucial role in maintaining proper ionic composition in the ear. The extracellular fluid, called endolymph, found in the cochlea of the mammalian inner ear is particularly unique due to its electrochemical properties. At an endocochlear potential of about +80 mV, signaling initiated by acoustic stimuli at the level of the hair cells is dependent on the unusually high potassium (K+ ) concentration of endolymph. There are ion channels and transporters that exists in the ear to ensure that K+ is continually being cycled into the stria media endolymph. This review is focused on the discussion of the molecular and genetic basis of previously and newly recognized ion channels and transporters that support sensory hair cell excitation based on recent knock-in and knock-out studies of these channels. This article also addresses the molecular and genetic defects and the pathophysiology behind Meniere's disease as well as how the dysregulation of these ion transporters can result in severe defects in hearing or even deafness. Understanding the role of ion channels and transporters in the auditory system will facilitate in designing effective treatment modalities against ear disorders including Meniere's disease and hearing loss. J. Cell. Physiol. 232: 743-758, 2017. © 2016 Wiley Periodicals, Inc.

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function.

Ear is a sensitive organ involved in hearing and balance function. The complex signaling network in the auditory system plays a crucial role in maintaining normal physiological function of the ear. The inner ear comprises a variety of host signaling pathways working in synergy to deliver clear sensory messages. Any disruption, as minor as it can be, has the potential to affect this finely tuned system with temporary or permanent sequelae including vestibular deficits and hearing loss. Mutations linked to auditory symptoms, whether inherited or acquired, are being actively researched for ways to reverse, silence, or suppress them. In this article, we discuss recent advancements in understanding the pathways involved in auditory system signaling, from hair cell development through transmission to cortical centers. Our review discusses Notch and Wnt signaling, cell to cell communication through connexin and pannexin channels, and the detrimental effects of reactive oxygen species on the auditory system. There has been an increased interest in the auditory community to explore the signaling system in the ear for hair cell regeneration. Understanding signaling pathways in the auditory system will pave the way for the novel avenues to regenerate sensory hair cells and restore hearing function. J. Cell. Physiol. 232: 2710-2721, 2017. © 2016 Wiley Periodicals, Inc.

Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis.

Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. © 2016 Wiley Periodicals, Inc.

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System.

The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. © 2015 Wiley Periodicals, Inc.

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions.

Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models.

OBJECTIVES: The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models. METHODS: A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. RESULTS: Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function. CONCLUSIONS: Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.

A systematic review of the association of Type I diabetes with sensorineural hearing loss.

OBJECTIVES: Type 1 diabetes (T1D) has been associated with several comorbidities such as ocular, renal, and cardiovascular complications. However, the effect of T1D on the auditory system and sensorineural hearing loss (SNHL) is still not clear. The aim of this study was to conduct a systematic review to evaluate whether T1D is associated with hearing impairment. METHODS: The databases PubMed, Science Direct, Scopus, and EMBASE were searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Three reviewers independently screened, selected, and extracted data. The Joanna Briggs Institute (JBI) Critical Appraisal Tools for Analytical cross-sectional and case-control studies were used to perform quality assessment and risk of bias analysis on eligible studies. RESULTS: After screening a total of 463 studies, 11 eligible original articles were included in the review to analyze the effects of T1D on the auditory system. The included studies comprised cross-sectional and case-control investigations. A total of 5,792 patients were evaluated across the 11 articles included. The majority of the studies showed that T1D was associated with hearing impairment compared to controls, including differences in PTAs and OAEs, increased mean hearing thresholds, altered acoustic reflex thresholds, and problems with the medial olivocochlear (MOC) reflex inhibitory effect. Significant risk factors included older age, increased disease duration, and higher HbA1C levels. CONCLUSIONS: This systematic review suggests that there is a correlation between T1D and impairment on the auditory system. A multidisciplinary collaboration between endocrinologists, otolaryngologists, and audiologists will lead to early detection of hearing impairment in people with T1D resulting in early intervention and better clinical outcomes in pursuit of improving the quality of life of affected individuals. REGISTRATION: This systematic review is registered in PROSPERO (CRD42023438576).

Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders.

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.

Incidence of Otolaryngological Manifestations in Individuals with Autism Spectrum Disorder: A Special Focus on Auditory Disorders.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by stereotyped and repetitive behavior patterns. In addition to neurological and behavioral problems, individuals with ASD commonly experience otolaryngological comorbidities. Individuals with ASD often have auditory disorders including hearing loss and auditory processing disorders such as central auditory processing disorder (CAPD), as well as both chronic and recurrent otitis media. These challenges negatively impact a person's ability to effectively communicate and may further impact their neurological functioning, particularly when not appropriately treated. Individuals diagnosed with ASD also have difficulty sleeping which contributes to increased irritability and may further aggravate the core behavioral symptoms of autism. The individuals with ASD also have a higher rate of sinusitis which contributes to the worsening of the autism behavior phenotype. The high prevalence of otolaryngological comorbidities in individuals with ASD warrants a better collaboration between their various healthcare providers and otolaryngologists with expertise in auditory, sleep, and sinus disorders in pursuit of improving the quality of life of affected individuals and their families/caregivers.

Vestibular Schwannoma and Tinnitus: A Systematic Review of Microsurgery Compared to Gamma Knife Radiosurgery.

Background: Vestibular schwannoma (VS) is a benign tumor of the eighth cranial nerve formed from neoplastic Schwann cells. Although VS can cause a variety of symptoms, tinnitus is one of the most distressing symptoms for patients and can greatly impact quality of life. The objective of this systematic review is to comprehensively examine and compare the outcomes related to tinnitus in patients undergoing treatment for VS. Specifically, it evaluates patient experiences with tinnitus following the removal of VS using the various surgical approaches of traditional surgical resection and gamma knife radiosurgery (GKS). By delving into various aspects such as the severity of tinnitus post-treatment, the duration of symptom relief, patient quality of life, new onset of tinnitus after VS treatment, and any potential complications or side effects, this review aims to provide a detailed analysis of VS treatment on tinnitus outcomes. Methods: Following PRISMA guidelines, articles were included from PubMed, Science Direct, Scopus, and EMBASE. Quality assessment and risk of bias analysis were performed using a ROBINS-I tool. Results: Although VS-associated tinnitus is variable in its intensity and persistence post-resection, there was a trend towards a decreased tinnitus burden in patients. Irrespective of the surgical approach or the treatment with GKS, there were cases of persistent or worsened tinnitus within the studied cohorts. Conclusion: The findings of this systematic review highlight the complex relationship between VS resection and tinnitus outcomes. These findings underscore the need for individualized patient counseling and tailored treatment approaches in managing VS-associated tinnitus. The findings of this systematic review may help in guiding clinicians towards making more informed and personalized healthcare decisions. Further studies must be completed to fill gaps in the current literature.

Landscape of NRXN1 Gene Variants in Phenotypic Manifestations of Autism Spectrum Disorder: A Systematic Review.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Recent research has increasingly focused on the genetic underpinnings of ASD, with the Neurexin 1 (NRXN1) gene emerging as a key player. This comprehensive systematic review elucidates the contribution of NRXN1 gene variants in the pathophysiology of ASD. Methods: The protocol for this systematic review was designed a priori and was registered in the PROSPERO database (CRD42023450418). A risk of bias analysis was conducted using the Joanna Briggs Institute (JBI) critical appraisal tool. We examined various studies that link NRXN1 gene disruptions with ASD, discussing both the genotypic variability and the resulting phenotypic expressions. Results: Within this review, there was marked heterogeneity observed in ASD genotypic and phenotypic manifestations among individuals with NRXN1 mutations. The presence of NRXN1 mutations in this population emphasizes the gene's role in synaptic function and neural connectivity. Conclusion: This review not only highlights the role of NRXN1 in the pathophysiology of ASD but also highlights the need for further research to unravel the complex genetic underpinnings of the disorder. A better knowledge about the multifaceted role of NRXN1 in ASD can provide crucial insights into the neurobiological foundations of autism and pave the way for novel therapeutic strategies.

Quality of Life, Neurosensory Disorders and Co-Occurring Medical Conditions in Individuals on the Spectrum, with a Special Focus on Females Diagnosed with Autism: A Systematic Review.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that has a high prevalence and a significant economic impact. Our knowledge regarding neurosensory disorders and co-occurring medical conditions in the ASD population is limited, particularly for autistic women. Most of the studies include male participants or do not make comparisons with their female counterparts. The objective of this systematic review article is to explore the quality of life as well as the prevalence of neurosensory disorders and co-occurring medical conditions in individuals on the spectrum, with a special focus on autistic females. The literature search was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42022330368). We concluded that numerous medical areas were of concern. Autistic females are more likely than their male counterparts with ASD to suffer from psychiatric conditions such as post-traumatic stress syndrome, depression, and eating disorders. They are also more likely to report GI-related disturbances and chronic pain. Further investigations are warranted to determine quality of life, as well as the prevalence and severity of neurosensory disorders in individuals with ASD, specifically studies comparing autistic females with their male counterparts. The information derived from these studies will help develop better support systems for individuals with autism, particularly females on the spectrum, in pursuit of improving their quality of life.

Modulation of Gut Microbiome as a Therapeutic Modality for Auditory Disorders.

The gut microbiome has been shown to play a pivotal role in health and disease. Recently, there has been increased interest within the auditory community to explore the role of the gut microbiome in the auditory system and its implications for hearing disorders such as sensorineural hearing loss (SNHL), otitis media, and tinnitus. Studies have suggested that modulating the gut microbiome using probiotics as well as with diets high in monounsaturated and omega-3 fatty acids is associated with a reduction in inflammation prevalence in auditory disorders. This review aims to evaluate the current literature on modulation of the gut microbiome and its effects on otological conditions. The probiotic conversion of nondigestible carbohydrates into short-chain fatty acids has been shown to provide benefits for improving hearing by maintaining an adequate vascular supply. For acute and secretory otitis media, studies have shown that a combination therapy of probiotics with a decreased dose of antibiotics yields better clinical outcomes than aggressive antibiotic treatment alone. Gut microbiome modulation also alters neurotransmitter levels and reduces neuroinflammation, which may provide benefits for tinnitus by preventing increased neuronal activity. Further studies are warranted to evaluate the efficacy of probiotics, natural health products, and micronutrients on auditory disorders, paving the way to develop novel interventions.

Recent advancements in noninvasive brain modulation for individuals with autism spectrum disorder.

Autism spectrum disorder is classified as a spectrum of neurodevelopmental disorders with an unknown definitive etiology. Individuals with autism spectrum disorder show deficits in a variety of areas including cognition, memory, attention, emotion recognition, and social skills. With no definitive treatment or cure, the main interventions for individuals with autism spectrum disorder are based on behavioral modulations. Recently, noninvasive brain modulation techniques including repetitive transcranial magnetic stimulation, intermittent theta burst stimulation, continuous theta burst stimulation, and transcranial direct current stimulation have been studied for their therapeutic properties of modifying neuroplasticity, particularly in individuals with autism spectrum disorder. Preliminary evidence from small cohort studies, pilot studies, and clinical trials suggests that the various noninvasive brain stimulation techniques have therapeutic benefits for treating both behavioral and cognitive manifestations of autism spectrum disorder. However, little data is available for quantifying the clinical significance of these findings as well as the long-term outcomes of individuals with autism spectrum disorder who underwent transcranial stimulation. The objective of this review is to highlight the most recent advancements in the application of noninvasive brain modulation technology in individuals with autism spectrum disorder.

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2-/- rats. We observed that the BBB permeability was significantly increased in Cntnap2-/- rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2-/- rats, suggesting oxidative stress. Brain sections from Cntnap2-/- rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2-/- rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2-/- rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.