بررسی بیان گیرنده NMDA و عملکردهای شناختی در کودکان مبتلا به اختلال نقص توجه و بیش فعالی: مطالعه تحلیلی مقایسه ای (مقاله علمی وزارت علوم)
درجه علمی: نشریه علمی (وزارت علوم)
آرشیو
چکیده
مقدمه: یافته های مطالعات بالینی، ژنتیکی و مدل حیوانی نشان داده اند که گیرنده های ((NMDA) N-methyl-D-aspartate) ممکن است نقش فعالی در بروز بسیاری از اختلالات اعصاب و روان داشته باشند و نقص درگیرنده های NMDA منجر به اختلال در تمرکز و بروز رفتار های تکانشگری می شود. سطح بیان پروتئین های NR1 و NR2 که از زیرواحد های اصلی گیرنده های NMDA می باشند در این مطالعه مورد سنجش قرار گرفت. روش کار: ابتدا آزمون K-SADS و تست هوش ریون گرفته شد، سپس آزمودنی ها در تعداد 70 نفر در دو گروه افراد مبتلا به بیش فعالی (50 نفر) با همسالان خود در گروه کنترل (20 نفر) وارد مطالعه شدند. تست IVA-2 انجام گرفت و از هر دو گروه، نمونه خونی گرفته و با استفاده از روش وسترن بلاتینگ، بیان زیرواحدهای NR1 و NR2 محاسبه گردید. یافته ها: نتایج نشان دادند، غلظت پروتئین های NR1 و NR2 در خون افراد دارای بیش فعالی به مقدار قابل توجه ای کمتر از همسالان خود در گروه کنترل می باشد. با توجه به نمرات بهره تمرکزی در تست IVA-2 که نشان دهنده کاهش بهره تمرکزی در افراد گروه آزمایش به نسبت گروه کنترل بود پس مشخص می کند که غلظت پایین تر زیرواحدهای NR1 و NR2 می تواند باعث کاهش بهره تمرکزی و نیز کاهش زیرواحدهای شناختی باشد. نتیجه گیری: این اختلاف معنا دار در نتایج این مطالعه، اثربخشی بیان زیرواحدهای NR1 و NR2 در گیرنده های NMDA و در نهایت سیستم گلوتاماترژیک را در اختلال نقص توجه و بیش فعالی، شدت آن و علائم شناختی مرتبط با آن، مشخص می کند که در نهایت می تواند منجر به تبیین مجدد مسیر دارویی و ایجاد پروتکل های درمان توان بخشی در این اختلال گردد.Investigating the expression of N-methyl-D-aspartate receptors and cognitive function in children with attention-deficit hyperactivity disorder: A comparative study
Introduction
N-methyl-D-aspartate (NMDA) receptors hold profound importance in shaping an individual’s mental and physical health. These receptors, forming heterotetrametric complexes, play a pivotal role in synaptic plasticity, learning, and memory. Dysfunction in NMDA receptors has been associated with a spectrum of neurological and psychiatric disorders, including Alzheimer’s disease, schizophrenia, depression, and Attention-Deficit Hyperactivity Disorder (ADHD). The intricate regulatory mechanisms of these receptors, involving subunit diversity, allow for fine-tuning of synaptic transmission. Therapeutically, drugs targeting NMDA receptors, such as ketamine for depression, underscore their crucial role in mental health. Ongoing research explores their involvement in physical health, with potential implications for conditions like ADHD. Understanding and modulating NMDA receptor function emerge as critical endeavors for promoting comprehensive well-being, highlighting the intricate interplay between molecular processes and overall health outcomes.
In this context, the present research aims to unravel the specific interplay between NMDA receptor subunits NR1 and NR2 and ADHD. It aims to elucidate the potential role of NR1 and NR2 receptors in the pathophysiology of ADHD and contribute valuable insights that may pave the way for more targeted therapeutic interventions in ADHD and potentially other neuropsychiatric disorders.
Methods
The study involved 70 male participants aged 6 to 15 years, comprising 50 individuals diagnosed with mixed ADHD and 20 age-matched healthy controls. Participants meeting DSM-IV criteria for mixed ADHD were recruited from the rehabilitation clinics in Tehran, Iran. Inclusion criteria specified ages between 6 and 15 years. Exclusively male participants were selected to minimize potential gender-related confounding factors. Additionally, individuals with a history of neurological or neuropsychological problems and severe physical illness were excluded from the research. Healthy controls were recruited through advertisements targeting children in some schools, screened, and matched for age and gender.
ADHD participants underwent a comprehensive diagnostic assessment conducted by an expert clinician involving pre-assessment questionnaires, semi-structured interviews aligned with DSM-5 criteria, and administration of the K-SADS-PL and IVA2 tests for enhanced diagnostic validity. The K-SADS-PL screening interview focused on ADHD symptoms, with responses rated on a scale. The IVA2 assessed attention and impulsivity through responses to auditory and visual stimuli and total attention quotient. Blood samples drawn without specific timing or fasting requirements were collected from both study and control groups, processed, and stored at -80#176;C. Serum samples were later used to quantify NR1 and NR2 receptor expression through western blotting, with fluorescence visualization and computer-assisted analysis software for relative abundance determination. All analyses were performed using SPSS software version 26.
Results
The investigation revealed noteworthy distinctions in the mean expression levels of NR1 and NR2 receptors between the experimental group (ADHD) and the healthy control group. Specifically, the mean expression of NR1 receptors in the ADHD group was found to be 97.7, significantly lower than the corresponding mean expression of 124.25 observed in the healthy control group, as indicated by the p-value of P<0.00001, denoting statistical significance at P<0.05. Similarly, the mean expression of NR2 receptors in the ADHD group, quantified at 154.6, demonstrated a significant variance from the mean expression of 173.25 in the healthy control group, corroborated by a p-value of P<.00001, thereby establishing statistical significance at P<0.05. These findings underscore the substantial disparities in the expression profiles of NMDA glutamate receptors in individuals with ADHD compared to their neurotypical counterparts, providing valuable insights into the molecular underpinnings of this neurodevelopmental disorder. The decrease in the expression of these proteins in the ADHD group causes a decrease in cognitive symptoms, including attention quotient, in this group compared to healthy people.
Conclusion
The current study revealed a significant link between ADHD and abnormal expression of NMDA glutamate receptors, particularly the NR1 and NR2 subunits, in the blood plasma of individuals with ADHD compared to healthy controls. This suggests a potential role for NMDA receptors in ADHD’s pathophysiology, implying that impaired NMDA receptor function may contribute to the disorder’s development. Dysfunctional NMDA receptors can impact dopamine and epinephrine levels in the brain, influencing ADHD symptoms. Notably, disruptions in NMDA receptors can lead to excessive and insufficient dopamine levels, contributing to hyperactivity, impulsivity, attention regulation difficulties, motivation, and focus issues. The findings highlight the need for a more comprehensive understanding of ADHD’s neurobiological foundations and suggest potential therapeutic avenues targeting NMDA receptor function. Additionally, the study contributes to personalized medicine in ADHD and has broader implications for understanding brain function in neuropsychiatric disorders influenced by glutamatergic signalling, offering insights that deepen our comprehension of ADHD, provide therapeutic potential, and contribute to a broader understanding of brain function in neuropsychiatric contexts.
Ethical consideration
Compliance with ethical guidelines
This article is extracted from the PhD dissertation with the approval ID IR.IUMS.REC.1398.1328. The research demonstrates adherence to ethical principles by ensuring adequate information provision, obtaining consent from participants, and upholding the principle of confidentiality concerning participants’ information. Only researchers were allowed to access the data, and all digital files were password-protected. All efforts were made to minimize any possible harm to the participants. The research protocol was designed to eliminate any physical, psychological, or emotional harm. Participants were not exposed to any additional stress or discomfort during the study. The research process allowed participants the freedom to withdraw from the study at any point, respecting their autonomy and commitment to ethical research practices.
Authors’ contribution
In this research, Mohammad Reza Zarrindast contributed to developing the initial idea and assisted with designing the study method and defining the hypothesis. Peyman Hassani Abharian assisted with diagnostic tests for cognitive features. Solmaz Khalifeh supervised the western blotting method, and Mohammad Nasehi contributed to the scientific discussion on data interpretation, and source support, and editing of the final draft.
Funding
The research was conducted without external financial support or funding. The first author provided all financial costs.
Acknowledgments
The authors express their gratitude to all the participants and people who facilitated the implementation of this research.
Conflict of interest
The authors declare that the research was conducted without any relationships that could potentially create a conflict of interest.
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