Neural Pathways Research Articles

Why Pimping Works: The Neurophysiology of Emotional Memories.

A time-honored medical ritual that combines emotion and cognition into a seamless consolidation of lucid memories is a feared teaching method in medical education. The resulting neurophysiology is explained from a neurosurgeon's perspective - equal parts guilt and dread as a prescription for an improved and sustained trainee fund of knowledge. Much of the available literature published with regard to pimping explores its pedagogy and use in medical practice. This review aims to explore the neurobehavioral and biological aspects of pimping in why it remains a popular teaching model. We describe the neuromodulatory process of integrating emotions and memory as observed during pimping. Additionally, we explore the neuronal pathways and circuits involved in memory encoding, consolidation, and retrieval. Finally, we explored theeffects of this methodology as it is currently used in the United States medical education system.

Neuroprotection of Transcranial Cortical and Peripheral Somatosensory Electrical Stimulation by Modulating a Common Neuronal Death Pathway in Mice with Ischemic Stroke.

Therapeutic electrical stimulation, such as transcranial cortical stimulation and peripheral somatosensory stimulation, is used to improve motor function in patients with stroke. We hypothesized that these stimulations exert neuroprotective effects during the subacute phase of ischemic stroke by regulating novel common signaling pathways. Male C57BL/6J mouse models of ischemic stroke were treated with high-definition (HD)-transcranial alternating current stimulation (tACS; 20 Hz, 89.1 A/mm2), HD-transcranial direct current stimulation (tDCS; intensity, 55 A/mm2; charge density, 66,000 C/m2), or electroacupuncture (EA, 2 Hz, 1 mA) in the early stages of stroke. The therapeutic effects were assessed using behavioral motor function tests. The underlying mechanisms were determined using transcriptomic and other biomedical analyses. All therapeutic electrical tools alleviated the motor dysfunction caused by ischemic stroke insults. We focused on electrically stimulating common genes involved in apoptosis and cell death using transcriptome analysis and chose 11 of the most potent targets (Trem2, S100a9, Lgals3, Tlr4, Myd88, NF-kB, STAT1, IL-6, IL-1β, TNF-α, and Iba1). Subsequent investigations revealed that electrical stimulation modulated inflammatory cytokines, including IL-1β and TNF-α, by regulating STAT1 and NF-kB activation, especially in amoeboid microglia; moreover, electrical stimulation enhanced neuronal survival by activating neurotrophic factors, including BDNF and FGF9. Therapeutic electrical stimulation applied to the transcranial cortical- or periphery-nerve level to promote functional recovery may improve neuroprotection by modulating a common neuronal death pathway and upregulating neurotrophic factors. Therefore, combining transcranial cortical and peripheral somatosensory stimulation may exert a synergistic neuroprotective effect, further enhancing the beneficial effects on motor deficits in patients with ischemic stroke.

Test-Retest Reliability of Tone Burst-Induced 500 Hz Air-Conduction Masseter Vestibular Evoked Myogenic Potential in Healthy Individuals.

: Masseter vestibular evoked myogenic potential (mVEMP) is a newly developed tool which is used to assess the vestibulo-trigeminal neural and saccular functioning pathways. Recently, this test was added to a full test battery for evaluating the brainstem of people with neurological disorders and other vestibular diseases. For any test to qualify as a standard test, the test must have high reliability across all testing windows. Hence, the present study focused on validating the reliability of mVEMP in a large population. : The study included 50 healthy participants with normal hearing. All the participants were tested using mVEMP and underwent retest within a month after the initial test. All parameters (latencies, peak-to-peak amplitude, asymmetric ratio) were observed for both sessions. To determine the statistically significant differences between and across the sessions, non-parametric tests such as Mann-Whitney U and Wilcoxon signed-rank tests were used. : The test-retest reliability of all parameters were observed. The reliability was fair-to-good for P11 and N21 latencies. The other parameters showed less significance. There were no significant differences in sex and ear comparisons between and across the sessions. : Our study demonstrated that the mVEMP is a reliable test which can be used to assess peripheral vestibular system dysfunction and neurological conditions.

Ocular Vestibular-Evoked Myogenic Potential Assists in the Differentiation of Multiple System Atrophy From Parkinson's Disease.

Vestibular-evoked myogenic potentials (VEMPs) can help in assessing otolithic neural pathway in the brainstem, which may also contribute to the cardiovascular autonomic function. Parkinson's disease (PD) is associated with altered VEMP responses; however, the associations between VEMP abnormalities and multiple system atrophy (MSA) remain unknown. Therefore, we compared the extent of otolith dysfunction using ocular (oVEMP) and cervical VEMPs between patients with MSA and PD. We analyzed the clinical features, VEMP, and head-up tilt table test (HUT) findings using the Finometer in 24 patients with MSA and 52 with de novo PD who had undergone neurotologic evaluation at a referral-based university hospital in South Korea from January 2021 to March 2023. MSA was associated with bilateral oVEMP abnormalities (odds ratio [95% confidence interval] = 9.19 [1.77-47.76], p = 0.008). The n1-p1 amplitude was negatively correlated with the Unified Multiple System Atrophy Rating Scale I-II score in patients with MSA (r = -0.571, p = 0.033), whereas it did not correlate with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-III score in patients with PD (r = -0.051, p = 0.687). The n1 latency was negatively correlated with maximum changes in systolic blood pressure within 15 s during HUT in patients with PD (r = -0.335, p = 0.040) but not in those with MSA (r = 0.277, p = 0.299). Bilaterally abnormal oVEMP responses may indicate the extent of brainstem dysfunction in MSA. oVEMP reflects the integrity of otolith-autonomic interplay, reliably assists in differentiating between MSA and PD, and helps infer clinical decline.

Functional relationship between peripheral thermosensation and behavioral thermoregulation.

Thermoregulation is a fundamental mechanism for maintaining homeostasis in living organisms because temperature affects essentially all biochemical and physiological processes. Effector responses to internal and external temperature cues are critical for achieving effective thermoregulation by controlling heat production and dissipation. Thermoregulation can be classified as physiological, which is observed primarily in higher organisms (homeotherms), and behavioral, which manifests as crucial physiological functions that are conserved across many species. Neuronal pathways for physiological thermoregulation are well-characterized, but those associated with behavioral regulation remain unclear. Thermoreceptors, including Transient Receptor Potential (TRP) channels, play pivotal roles in thermoregulation. Mammals have 11 thermosensitive TRP channels, the functions for which have been elucidated through behavioral studies using knockout mice. Behavioral thermoregulation is also observed in ectotherms such as the fruit fly, Drosophila melanogaster. Studies of Drosophila thermoregulation helped elucidate significant roles for thermoreceptors as well as regulatory actions of membrane lipids in modulating the activity of both thermosensitive TRP channels and thermoregulation. This review provides an overview of thermosensitive TRP channel functions in behavioral thermoregulation based on results of studies involving mice or Drosophila melanogaster.

A guide to selecting high-performing antibodies for Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D) for use in Western Blot, immunoprecipitation and immunofluorescence

Protein phosphatase 2A is a serine/threonine phosphatase with activity dependent on an associated regulatory subunit, serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta (δ) isoform (PPP2R5D). PPP2R5D is the δ isoform in the B56 family of regulatory subunits. Abundantly expressed in the brain and involved in a broad range of cellular processes, PPP2R5D plays an essential role in modulating key neuronal pathways and signalling. Pathogenic mutations in the PPP2R5D gene are linked to clinical symptoms characterized by neurodevelopmental delay, intellectual disability, and autism spectrum disorders. The etiology of these genetic disorders remains unknown, which can partly be due to the lack of independently characterized antibodies. Here we have characterized six PPP2R5D commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

A wound-induced differentiation trajectory for neurons

Animals capable of whole-body regeneration can replace any missing cell type and regenerate fully functional new organs, including new brains, de novo. The regeneration of a new brain requires the formation of diverse neural cell types and their assembly into an organized structure with correctly wired circuits. Recent work in various regenerative animals has revealed transcriptional programs required for the differentiation of distinct neural subpopulations, however, how these transcriptional programs are initiated in response to injury remains unknown. Here, we focused on the highly regenerative acoel worm, Hofstenia miamia, to study wound-induced transcriptional regulatory events that lead to the production of neurons and subsequently a functional brain. Footprinting analysis using chromatin accessibility data on a chromosome-scale genome assembly revealed that binding sites for the Nuclear Factor Y (NFY) transcription factor complex were significantly bound during regeneration, showing a dynamic increase in binding within one hour upon amputation specifically in tail fragments, which will regenerate a new brain. Strikingly, NFY targets were highly enriched for genes with neuronal function. Single-cell transcriptome analysis combined with functional studies identified soxC+ stem cells as a putative progenitor population for multiple neural subtypes. Further, we found that wound-induced soxC expression is likely under direct transcriptional control by NFY, uncovering a mechanism for the initiation of a neural differentiation pathway by early wound-induced binding of a transcriptional regulator.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.

The Impact of Physical Activity on Gut Microbiota: An In-Depth Literature Review

Introduction. The human body is home to a diverse community of microorganisms known as the microbiota. These microorganisms, including bacteria, fungi, and viruses, play crucial roles in maintaining overall health. They colonize the digestive tract shortly after birth, and the composition of the gut microbiota changes throughout an individual's life, largely influenced by diet and physical activity. Breastfeeding has long-term beneficial effects on the gut microbiota and gene expression in intestinal cells. Regular exercise not only improves cardiovascular and respiratory health but also affects metabolic, immunological, neural, and microbial pathways. This review explores how diet and physical activity impact the composition and diversity of gut microbiota, highlighting important findings and their implications for health. Aim of study. This study aims to review how physical activity influences gut microbiota, investigating the effects of different types and intensities of exercise on microbial composition and diversity, and their implications for overall health. Materials and methods. A non-systematic examination of the scientific literature was conducted using specific keywords such as gut microbiota, physical activity, sport, and microbiome. The examination took place on PubMed, with scrutiny of a total of 31 references published up to 2023. Conclusions. This review highlights the crucial role of gut microbiota in maintaining good health and its complex interaction with diet and physical activity. Regular exercise has a positive impact on the diversity of microbiota, especially when started at a young age. Imbalance in gut bacteria is linked to various diseases, underscoring the significance of a healthy microbiome. Encouraging physical activity and a nutritious diet can improve gut health, and more research is needed to understand the mechanisms and potential health indicators involved.

Constraining current neuroanatomical models of reading: the view from Arabic.

There is a growing interest in imaging understudied orthographies to unravel their neuronal correlates and their implications for existing computational and neuroanatomical models. Here, we review current brain mapping literature about Arabic words. We first offer a succinct description of some unique linguistic features of Arabic that challenge current cognitive models of reading. We then appraise the existing functional neuroimaging studies that investigated written Arabic word processing. Our review revealed that (1) Arabic is still understudied, (2) the most investigated features concerned the effects of vowelling and diglossia in Arabic reading, (3) findings were not always discussed in the light of existing reading models such as the dual route cascaded, the triangle, and the connectionist dual process models, and (4) current evidence is unreliable when it comes to the exact neuronal pathways that sustain Arabic word processing. Overall, despite the fact that Arabic has some unique linguistic features that challenge and ultimately enrich current reading models, the existing functional neuroimaging literature falls short of offering a reliable evidence about brain networks of Arabic reading. We conclude by highlighting the need for more systematic studies of the linguistic features of Arabic to build theoretical and neuroanatomical models that are concurrently specific and general.

Neural pathways that compel us to scratch an itch

Neural pathways that compel us to scratch an itch

A Systematic Review & Meta-Analysis on Criteria for Transcranial Motor Evoked Potential for Intraoperative Neuromonitoring during Spine Surgeries

Abstract Background Spine Surgery is the definitive treatment and indication for many traumatic spine illnesses, as well as several pathologies and deformities. Surgery in such a vital organ, formed in its core of the neural pathway that controls the whole of the human body, must be as safe, and least risky as possible, so as to prevent injuries to the neural pathway, or the surrounding vessels, or vital organs. Such great importance of the spine and the spinal cord, has urged surgeons and researchers to create techniques through which spine surgeries are well monitored, and the efficacy and normal physiology is well assessed intraoperatively. Objective to conduct a systematic review and meta-analysis of what has been published of the studies using transcranial motor evoked potential for intraoperative neuromonitoring during spine surgeries. This is for acquiring the best criteria for transcranial motor evoked potential (TcMEP) utilization for intraoperative neuromonitoring, as well as identifying the most accurate alarm point for TcMEP during intraoperative neuromonitoring. Patients and Methods a comprehensive and detailed search of literature was conducted through the Pubmed, Google Scholar, and Research Gate databases including articles related to intraoperative neuromonitoring modalities and transcranial motor evoked potential alarm points and criteria. Searches were performed with a combination of MeSH (medical subject headings). Only Studies published in the English Language with no lower date limit were included. The following search string was used in all databases; (“Intraoperative Neuromonitoring” or “Transcranial Motor Evoked Potential”). Results In a prospective study conducted in 2018, performed on 2867 patients, using a 70 % decrease in amplitude of the TcMEP curve as an alarm point during high-risk spinal surgeries, the number of true positive to false positive cases was found to be 126/234, while the number of true negative cases to false negative cases was found to be 2362/9 cases in total. The study demonstrates the necessity of intraoperative neuromonitoring for high-risk spinal surgery. 136 cases in this study were identified as rescue cases, as intraoperative TcMEP alert occurred and intraoperative maneuverings were done to overcome those alerts, hence hindering occurrence of postoperative neural deficit. Conclusion As regards different TcMEP alarm point values, it has been concluded that an alarm point of 50-60% decrease in amplitude of TcMEP is a more sensitive alarm point, than a higher value alarm point of the same modality. An alarm point of > 70% decrease in amplitude has a much less sensitivity value than lower alarm points, which in turn will result in a lot of missed adverse events, and a higher percentage of false negative values.

Cellular and circuit architecture of the lateral septum for reward processing

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Chemical Memory in Primitive Organisms: Evolutionary Insights and Mechanistic Perspectives

Memory, the cornerstone of adaptive behavior, has been extensively studied within the confines of neural systems. A comprehensive literature review was conducted using key academic databases such as PubMed, Web of Science, and Google Scholar. The methodology prioritized peer-reviewed papers, reviews, and primary research, with a particular emphasis on articles relevant to chemical memory in primitive organisms. This review sheds light on the less-explored territory of chemical memory in primitive organisms. From the complex neural pathways in humans to the basic chemical interactions in bacteria and protozoa, this study underscores the evolutionary significance and ubiquity of information storage in biology. A notable highlight is the exploration of the ability of plants to adaptively respond to their environment despite lacking a central nervous system, emphasizing the role of epigenetic markers in stress memory. In organisms devoid of advanced neural systems, chemical reactions, and interactions pave the way for memory mechanisms, offering insight into the foundational building blocks of memory. The findings presented challenges in traditional neuro-centric views, broadening our understanding of memory and highlighting its pivotal role in the evolutionary tapestry of life.

Impact of social reward on stress circuit function and regulation: Path differences between value affirmation and emotional support

BackgroundAs two typical types of social rewards, both value affirmation and emotional support could alleviate acute stress response, but it is not clear whether they can impact stress circuit function and regulation through different neural pathways. MethodSixty-two participants were randomly assigned to the value affirmation, emotional support, and non-reward conditions, then administered an adapted version of the ScanSTRESS paradigm. Participants’ subjective reports of uncontrollability and social evaluative threat were measured to explore the mitigation of stress by social rewards at the behavioral level. Meanwhile, their acute salivary cortisol response to stress was compared among different social reward conditions. Furthermore, we computed linear contrasts for performance (vs relaxation) and reward (vs non-reward) and used psychophysiological interaction (PPI) analysis to explore the impact of social reward on stress circuit function and regulation. ResultsBoth value affirmation and emotional support conditions reduced subjective reports of uncontrollability and social evaluation threat, but not cortisol response to stress. Furthermore, value affirmation reduced uncontrollability by enhancing putamen activation, whereas emotional support reduced social evaluation threat by enhancing putamen activation. More importantly, during stress, value affirmation enhanced the functional connectivity of the putamen-hippocampus and putamen-angular gyrus (AG), whereas emotional support enhanced the functional connectivity of the putamen-ventrolateral prefrontal cortex (vlPFC) and putamen-temporal pole mid, compared to the non-reward condition. ConclusionValue affirmation and emotional support alleviated acute stress response in different neural pathways. These findings suggested a precise categorization of social reward in intervention of a range of adverse psychological and physiological responses caused by stress.

Long-term high fructose intake reprograms the circadian transcriptome and disrupts homeostasis in mouse extra-orbital lacrimal glands

This study aims to explore the effects of long-term high fructose intake (LHFI) on the structure, functionality, and physiological homeostasis of mouse extra-orbital lacrimal glands (ELGs), a critical component of ocular health. Our findings reveal significant reprogramming of the circadian transcriptome in ELGs following LHFI, alongside the activation of specific inflammatory pathways, as well as metabolic and neural pathways. Notably, LHFI resulted in increased inflammatory infiltration, enhanced lipid deposition, and reduced nerve fiber density in ELGs compared to controls. Functional assessments indicated a marked reduction in lacrimal secretion following cholinergic stimulation in LHFI-treated mice, suggesting impaired gland function. Overall, our results suggest that LHFI disrupts lacrimal gland homeostasis, potentially leading to dry eye disease by altering its structure and secretory function. These insights underscore the profound impact of dietary choices on ocular health and highlight the need for strategies to mitigate these risks.

Nanosecond Transient IR Spectroscopy of Halorhodopsin in Living Cells.

The ability to track minute changes of a single amino acid residue in a cellular environment is causing a paradigm shift in the attempt to fully understand the responses of biomolecules that are highly sensitive to their environment. Detecting early protein dynamics in living cells is crucial to understanding their mechanisms, such as those of photosynthetic proteins. Here, we elucidate the light response of the microbial chloride pump NmHR from the marine bacterium Nonlabens marinus, located in the membrane of living Escherichia coli cells, using nanosecond time-resolved UV/vis and IR absorption spectroscopy over the time range from nanoseconds to seconds. Transient structural changes of the retinal cofactor and the surrounding apoprotein are recorded using light-induced time-resolved UV/vis and IR difference spectroscopy. Of particular note, we have resolved the kinetics of the transient deprotonation of a single cysteine residue during the photocycle of NmHR out of the manifold of molecular vibrations of the cells. These findings are of high general relevance, given the successful development of optogenetic tools from photoreceptors to interfere with enzymatic and neuronal pathways in living organisms using light pulses as a noninvasive trigger.

Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.

Gut-Brain Axis: Investigating the Effects of Gut Health on Cognitive Functioning in Adults.

The gut-brain axis is a bidirectional communication network linking the gastrointestinal tract and the central nervous system via neuronal, hormonal, and antibody signaling pathways. Central to this connection is gut health, encompassing the balance and functionality of gut microbiota, which significantly impacts on mental and cognitive health. This study investigates the association between gut health and cognitive functioning in adults, highlighting the mechanisms by which gut microbiota influence brain health. To examine the effects of gut health on adult cognitive performance, with a focus on the processes by which gut microbiota impacts brain health. A quantitative cross-sectional study was conducted in Islamabad from January 2024 to April 2024, involving 140 adult participants. Data were collected using a comprehensive 16-item gut health questionnaire and the cognition self-assessment rating scale (C-SARS). The psychometric properties of these scales were assessed, and the data were analyzed using Statistical Product and Service Solutions (SPSS, v26; IBM SPSS Statistics for Windows, Armonk, NY). Analytical and descriptive statistics, including regression, chi-square, independent sample t-tests, and mean and standard deviation, were applied. The study found moderate associations between gut health and cognitive performance, particularly in memory and processing speed (R² = 0.17, β = -1.9, p = 0.12 for general cognition; R² = 0.01, β = -0.98, p = 0.02 for memory; R² = 0.03, β = -0.18, p = 0.03 for processing speed). Gender and marital status differences were significant, with males exhibiting better gut health scores than females (M = 34.1, SD = 3.2 vs. M = 31.2, SD = 3.2, p = 0.00), and singles showing better cognitive performance compared to married individuals (M = 9.4, SD = 5.4 vs. M = 6.5, SD = 3.7, p = 0.03). The study highlights significant associations between gut health and cognitive functions, suggesting that gut microbiota composition can influence cognitive performance. Gender and marital status differences underscore the need to consider individual differences in gut-brain axis research. Future studies should replicate these findings in larger samples and explore gut microbiota-targeted interventions for cognitive health enhancement.

Phytocannabinoids as Potential Multitargeting Neuroprotectants in Alzheimer's Disease.

The Endocannabinoid System (ECS) is a well-studied system that influences a variety of physiological activities. It is evident that the ECS plays a significant role in metabolic activities and also has some neuroprotective properties. In this review, we emphasize several plant-derived cannabinoids such as β-caryophyllene (BCP), Cannabichromene (CBC), Cannabigerol (CBG), Cannabidiol (CBD), and Cannabinol (CBN), which are known to have distinctive modulation abilities of ECS. In Alzheimer's disease (AD), the activation of ECS may provide neuroprotection by modulating certain neuronal circuitry pathways through complex molecular cascades. The present article also discusses the implications of cannabinoid receptors (CB1 and CB2) as well as cannabinoid enzymes (FAAH and MAGL) modulators in AD. Specifically, CBR1 or CB2R modulations result in reduced inflammatory cytokines such as IL-2 and IL-6, as well as a reduction in microglial activation, which contribute to an inflammatory response in neurons. Furthermore, naturally occurring cannabinoid metabolic enzymes (FAAH and MAGL) inhibit the NLRP3 inflammasome complex, which may offer significant neuroprotection. In this review, we explored the multi-targeted neuroprotective properties of phytocannabinoids and their possible modulations, which could offer significant benefits in limiting AD.