Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer's Disease Treatment.

Despite decades of rigorous research and numerous clinical trials, Alzheimer's disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aß plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.

Lidocaine-Liposomes-A Promising Frontier for Transdermal Pain Management.

(1) Background: We aim to develop novel gel formulations for transdermal drug delivery systems in acute and inflammatory pain therapy. (2) Methods: We induced inflammation by the injection of λ-carrageenan on the hind paw of 80 Wistar male rats. The animals were randomized into eight groups of 10 rats each: C (placebo gel), E (EMLATM), L (lidocaine 2%), L-CD (lidocaine + cyclodextrin 2.5%), L-LP (lidocaine + liposomes 1.7%), L-CS (lidocaine + chitosan 4%), L-CSh (lidocaine + chitosan hydrochloride), and L-CS-LP (lidocaine + chitosan + liposomes). The behavior response was determined with a hot plate, cold plate, and algesimeter, each being performed at 30, 60, 120, 180, and 240 min after pain induction. At the end of the experiment, tissue samples were collected for histological assessment. (3) Results: L-LP had the greatest anesthetic effects, which was proven on the cold plate test compared to placebo and EMLATM (all p ≤ 0.001). L-CS-LP had a significant effect on cold plate evaluation compared to placebo (p ≤ 0.001) and on hot plate evaluation compared to EMLATM (p = 0.018). (4) Conclusions: L-LP is a new substance with a substantial analgesic effect demonstrated by the cold plate in the first 120 min. Further studies with more animals are needed to determine the maximum doses that can be applied for a better analgesia with minimum side effects.

The Role of the NF-kB Pathway in Intracranial Aneurysms.

The pathophysiology of intracranial aneurysms (IA) has been proven to be closely linked to hemodynamic stress and inflammatory pathways, most notably the NF-kB pathway. Therefore, it is a potential target for therapeutic intervention. In the present review, we investigated alterations in the vascular smooth muscle cells (VSMCs), extracellular matrix, and endothelial cells by the mediators implicated in the NF-kB pathway that lead to the formation, growth, and rupture of IAs. We also present an overview of the NF-kB pathway, focusing on stimuli and transcriptional targets specific to IAs, as well as a summary of the current strategies for inhibiting NF-kB activation in IAs. Our report adds to previously reported data and future research directions for treating IAs using compounds that can suppress inflammation in the vascular wall.

Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer's Disease.

The incidence of neurodegenerative diseases, such as Alzheimer's disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. The lack of a safe and effective causal therapy in cognitive decline is an aggravating factor and requires investigations into the repurposing of commonly used drugs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new and efficient class of hypoglycemic drugs and, due to their pleiotropic effects, have indications that go beyond diabetes. There is emerging data from murine studies that SGLT2i can cross the blood-brain barrier and may have neuroprotective effects, such as increasing the brain-derived neurotrophic factor (BDNF), reducing the amyloid burden, inhibiting acetylcholinesterase (AChE) and restoring the circadian rhythm in the mammalian target of rapamycin (mTOR) activation. The current study investigates the effect of an SGLT2i and donepezil, under a separate or combined 21-day treatment on AD-relevant behaviors and brain pathology in mice. The SGLT2i canagliflozin was found to significantly improve the novelty preference index and the percentage of time spent in the open arms of the maze in the novel object recognition and elevated plus maze test, respectively. In addition, canagliflozin therapy decreased AChE activity, mTOR and glial fibrillary acidic protein expression. The results also recorded the acetylcholine M1 receptor in canagliflozin-treated mice compared to the scopolamine group. In the hippocampus, the SGLT2i canagliflozin reduced the microgliosis and astrogliosis in males, but not in female mice. These findings emphasize the value of SGLT2i in clinical practice. By inhibiting AChE activity, canagliflozin represents a compound that resembles AD-registered therapies in this respect, supporting the need for further evaluation in dementia clinical trials.

A Nanostructured Protein Filtration Device for Possible Use in the Treatment of Alzheimer's Disease-Concept and Feasibility after In Vivo Tests.

BACKGROUND: Alzheimer's disease (AD), along with other neurodegenerative disorders, remains a challenge for clinicians, mainly because of the incomplete knowledge surrounding its etiology and inefficient therapeutic options. Considering the central role of amyloid beta (Aß) in the onset and evolution of AD, Aß-targeted therapies are among the most promising research directions. In the context of decreased Aß elimination from the central nervous system in the AD patient, the authors propose a novel therapeutic approach based on the "Cerebrospinal Fluid Sink Therapeutic Strategy" presented in previous works. This article aims to demonstrate the laborious process of the development and testing of an effective nanoporous ceramic filter, which is the main component of an experimental device capable of filtrating Aß from the cerebrospinal fluid in an AD mouse model. METHODS: First, the authors present the main steps needed to create a functional filtrating nanoporous ceramic filter, which represents the central part of the experimental filtration device. This process included synthesis, functionalization, and quality control of the functionalization, which were performed via various spectroscopy methods and thermal analysis, selectivity measurements, and a biocompatibility assessment. Subsequently, the prototype was implanted in APP/PS1 mice for four weeks, then removed, and the nanoporous ceramic filter was tested for its filtration capacity and potential structural damages. RESULTS: In applying the multi-step protocol, the authors developed a functional Aß-selective filtration nanoporous ceramic filter that was used within the prototype. All animal models survived the implantation procedure and had no significant adverse effects during the 4-week trial period. Post-treatment analysis of the nanoporous ceramic filter showed significant protein loading, but no complete clogging of the pores. CONCLUSIONS: We demonstrated that a nanoporous ceramic filter-based system that filtrates Aß from the cerebrospinal fluid is a feasible and safe treatment modality in the AD mouse model. The presented prototype has a functional lifespan of around four weeks, highlighting the need to develop advanced nanoporous ceramic filters with anti-biofouling properties to ensure the long-term action of this therapy.

Complexes of Ibuprofen Thiazolidin-4-One Derivatives with ß-Cyclodextrin: Characterization and In Vivo Release Profile and Biological Evaluation.

Generally, NSAIDs are weakly soluble in water and contain both hydrophilic and hydrophobic groups. One of the most widely used NSAIDs is ibuprofen, which has a poor solubility and high permeability profile. By creating dynamic, non-covalent, water-soluble inclusion complexes, cyclodextrins (CDs) can increase the dissolution rate of low aqueous solubility drugs, operating as a drug delivery vehicle, additionally contributing significantly to the chemical stability of pharmaceuticals and to reducing drug-related irritability. In order to improve the pharmacological and pharmacokinetics profile of ibuprofen, new thiazolidin-4-one derivatives of ibuprofen (4b, 4g, 4k, 4m) were complexed with ß-CD, using co-precipitation and freeze-drying. The new ß-CD complexes (ß-CD-4b, ß-CD-4g, ß-CD-4k, ß-CD-4m) were characterized using scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction and a phase solubility test. Using the AutoDock-VINA algorithm included in YASARA-structure software, we investigated the binding conformation of ibuprofen derivatives to ß-CD and measured the binding energies. We also performed an in vivo biological evaluation of the ibuprofen derivatives and corresponding ß-CD complexes, using analgesic/anti-inflammatory assays, as well as a release profile. The results support the theory that ß-CD complexes (ß-CD-4b, ß-CD-4g, ß-CD-4k, ß-CD-4m) have a similar effect to ibuprofen derivatives (4b, 4g, 4k, 4m). Moreover, the ß-CD complexes demonstrated a delayed release profile, which provides valuable insights into the drug-delivery area, focused on ibuprofen derivatives.

The Skin and Natural Cannabinoids-Topical and Transdermal Applications.

The chemical constituents of the Cannabis plant known as cannabinoids have been extensively researched for their potential therapeutic benefits. The use of cannabinoids applied to the skin as a potential method for both skin-related benefits and systemic administration has attracted increasing interest in recent years. This review aims to present an overview of the most recent scientific research on cannabinoids used topically, including their potential advantages for treating a number of skin conditions like psoriasis, atopic dermatitis, and acne. Additionally, with a focus on the pharmacokinetics and security of this route of administration, we investigate the potential of the transdermal delivery of cannabinoids as a method of systemic administration. The review also discusses the restrictions and difficulties related to the application of cannabinoids on the skin, emphasizing the potential of topical cannabinoids as a promising route for both localized and systemic administration. More studies are required to fully comprehend the efficacy and safety of cannabinoids in various settings.

Should oncologists trust cannabinoids?

Cannabis enjoyed a "golden age" as a medicinal product in the late 19th, early 20th century, but the increased risk of overdose and abuse led to its criminalization. However, the 21st century have witnessed a resurgence of interest and a large body of literature regarding the benefits of cannabinoids have emerged. As legalization and decriminalization have spread around the world, cancer patients are increasingly interested in the potential utility of cannabinoids. Although eager to discuss cannabis use with their oncologist, patients often find them to be reluctant, mainly because clinicians are still not convinced by the existing evidence-based data to guide their treatment plans. Physicians should prescribe cannabis only if a careful explanation can be provided and follow up response evaluation ensured, making it mandatory for them to be up to date with the positive and also negative aspects of the cannabis in the case of cancer patients. Consequently, this article aims to bring some clarifications to clinicians regarding the sometimes-confusing various nomenclature under which this plant is mentioned, current legislation and the existing evidence (both preclinical and clinical) for the utility of cannabinoids in cancer patients, for either palliation of the associated symptoms or even the potential antitumor effects that cannabinoids may have.

360-Degree Perspectives on Obesity.

Alarming statistics show that the number of people affected by excessive weight has surpassed 2 billion, representing approximately 30% of the world's population. The aim of this review is to provide a comprehensive overview of one of the most serious public health problems, considering that obesity requires an integrative approach that takes into account its complex etiology, including genetic, environmental, and lifestyle factors. Only an understanding of the connections between the many contributors to obesity and the synergy between treatment interventions can ensure satisfactory outcomes in reducing obesity. Mechanisms such as oxidative stress, chronic inflammation, and dysbiosis play a crucial role in the pathogenesis of obesity and its associated complications. Compounding factors such as the deleterious effects of stress, the novel challenge posed by the obesogenic digital (food) environment, and the stigma associated with obesity should not be overlooked. Preclinical research in animal models has been instrumental in elucidating these mechanisms, and translation into clinical practice has provided promising therapeutic options, including epigenetic approaches, pharmacotherapy, and bariatric surgery. However, more studies are necessary to discover new compounds that target key metabolic pathways, innovative ways to deliver the drugs, the optimal combinations of lifestyle interventions with allopathic treatments, and, last but not least, emerging biological markers for effective monitoring. With each passing day, the obesity crisis tightens its grip, threatening not only individual lives but also burdening healthcare systems and societies at large. It is high time we took action as we confront the urgent imperative to address this escalating global health challenge head-on.

A novel device and system concept for therapeutic plasma exchange in rats.

INTRODUCTION: Therapeutic plasma exchange (TPE) has been developed more than 100 years ago in an animal model and adapted to humans 30 years later. Since then, the TPE research on animal models is lacking, mainly due to difficulties raised by the scaling of the plasmapheresis unit so that the animal's cardiovascular parameters are not considerably affected. METHODS: The system concept of a novel TPE device with continuous hemodynamic monitoring in small rodent models has been used. RESULTS: A continuum TPE unit for rats has been developed, able to produce up to 95% plasma exchange rate without any TPE-related hemodynamic impairment, monitored up to 35 days after the procedure. CONCLUSION: The TPE unit for rats was able to produce 95% plasma exchange rate in non-anesthetized animals, enabling a full translation of the human TPE into an animal model. The newly developed plasmapheresis unit enable a wide range of more accurate preclinical evaluation, with cardiac parameters monitoring, using small rodents in awaken state.

Bone Cells Metabolic Changes Induced by Ageing.

Bone is a living organ that exhibits active metabolic processes, presenting constant bone formation and resorption. The bone cells that maintain local homeostasis are osteoblasts, osteoclasts, osteocytes and bone marrow stem cells, their progenitor cells. Osteoblasts are the main cells that govern bone formation, osteoclasts are involved in bone resorption, and osteocytes, the most abundant bone cells, also participate in bone remodeling. All these cells have active metabolic activities, are interconnected and influence each other, having both autocrine and paracrine effects. Ageing is associated with multiple and complex bone metabolic changes, some of which are currently incompletely elucidated. Ageing causes important functional changes in bone metabolism, influencing all resident cells, including the mineralization process of the extracellular matrix. With advancing age, a decrease in bone mass, the appearance of specific changes in the local microarchitecture, a reduction in mineralized components and in load-bearing capacity, as well as the appearance of an abnormal response to different humoral molecules have been observed. The present review points out the most important data regarding the formation, activation, functioning, and interconnection of these bone cells, as well as data on the metabolic changes that occur due to ageing.

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications.

Intrathecal pseudodelivery of drugs is a novel route to administer medications to treat neurodegenerative diseases based on the CSF-sink therapeutic strategy by means of implantable devices. While the development of this therapy is still in the preclinical stage, it offers promising advantages over traditional routes of drug delivery. In this paper, we describe the rationale of this system and provide a technical report on the mechanism of action, that relies on the use of nanoporous membranes enabling selective molecular permeability. On one side, the membranes do not permit the crossing of certain drugs; whereas, on the other side, they permit the crossing of target molecules present in the CSF. Target molecules, by binding drugs inside the system, are retained or cleaved and subsequently eliminated from the central nervous system. Finally, we provide a list of potential indications, the respective molecular targets, and the proposed therapeutic agents.

Brugada Syndrome: From Molecular Mechanisms and Genetics to Risk Stratification.

Brugada syndrome (BrS) is a rare hereditary arrhythmia disorder, with a distinctive ECG pattern, correlated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD) in young adults. BrS is a complex entity in terms of mechanisms, genetics, diagnosis, arrhythmia risk stratification, and management. The main electrophysiological mechanism of BrS requires further research, with prevailing theories centered on aberrant repolarization, depolarization, and current-load match. Computational modelling, pre-clinical, and clinical research show that BrS molecular anomalies result in excitation wavelength (k) modifications, which eventually increase the risk of arrhythmia. Although a mutation in the SCN5A (Sodium Voltage-Gated Channel Alpha Subunit 5) gene was first reported almost two decades ago, BrS is still currently regarded as a Mendelian condition inherited in an autosomal dominant manner with incomplete penetrance, despite the recent developments in the field of genetics and the latest hypothesis of additional inheritance pathways proposing a more complex mode of inheritance. In spite of the extensive use of the next-generation sequencing (NGS) technique with high coverage, genetics remains unexplained in a number of clinically confirmed cases. Except for the SCN5A which encodes the cardiac sodium channel NaV1.5, susceptibility genes remain mostly unidentified. The predominance of cardiac transcription factor loci suggests that transcriptional regulation is essential to the Brugada syndrome's pathogenesis. It appears that BrS is a multifactorial disease, which is influenced by several loci, each of which is affected by the environment. The primary challenge in individuals with a BrS type 1 ECG is to identify those who are at risk for sudden death, researchers propose the use of a multiparametric clinical and instrumental strategy for risk stratification. The aim of this review is to summarize the latest findings addressing the genetic architecture of BrS and to provide novel perspectives into its molecular underpinnings and novel models of risk stratification.

The Roles of Imaging Biomarkers in the Management of Chronic Neuropathic Pain.

Chronic neuropathic pain (CNP) affects around 10% of the general population and has a significant social, emotional, and economic impact. Current diagnosis techniques rely mainly on patient-reported outcomes and symptoms, which leads to significant diagnostic heterogeneity and subsequent challenges in management and assessment of outcomes. As such, it is necessary to review the approach to a pathology that occurs so frequently, with such burdensome and complex implications. Recent research has shown that imaging methods can detect subtle neuroplastic changes in the central and peripheral nervous system, which can be correlated with neuropathic symptoms and may serve as potential markers. The aim of this paper is to review available imaging methods used for diagnosing and assessing therapeutic efficacy in CNP for both the preclinical and clinical setting. Of course, further research is required to standardize and improve detection accuracy, but available data indicate that imaging is a valuable tool that can impact the management of CNP.

Nanoporous Membranes for the Filtration of Proteins from Biological Fluids: Biocompatibility Tests on Cell Cultures and Suggested Applications for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease has a significant epidemiological and socioeconomic impact, and, unfortunately, the extensive research focused on potential curative therapies has not yet proven to be successful. However, in recent years, important steps have been made in the development and functionalization of nanoporous alumina membranes, which might be of great interest for medical use, including the treatment of neurodegenerative diseases. In this context, the aim of this article is to present the synthesis and biocompatibility testing of a special filtrating nano-membrane, which is planned to be used in an experimental device for Alzheimer's disease treatment. METHODS: Firstly, the alumina nanoporous membrane was synthesized via the two-step anodizing process in oxalic acid-based electrolytes and functionalized via the atomic layer deposition technique. Subsequently, quality control tests (spectrophotometry and potential measurements), toxicity, and biocompatibility tests (cell viability assays) were conducted. RESULTS: The proposed alumina nanoporous membrane proved to be efficient for amyloid-beta filtration according to the permeability studies conducted for 72 h. The proposed membrane has proven to be fully compatible with the tested cell cultures. CONCLUSIONS: The proposed alumina nanoporous membrane model is safe and could be incorporated into implantable devices for further in vivo experiments and might be an efficient therapeutic approach for Alzheimer's disease.

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases.

The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.

In Vitro Modeling of the Blood-Brain Barrier for the Study of Physiological Conditions and Alzheimer's Disease.

The blood-brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer's disease. Thus, a deeper understanding of the BBB's structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural-functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer's disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality.

Exploring the Involvement of the Amyloid Precursor Protein A673T Mutation against Amyloid Pathology and Alzheimer's Disease in Relation to Therapeutic Editing Tools.

Alzheimer's disease (AD) is biologically defined as a complex neurodegenerative condition with a multilayered nature that leads to a progressive decline in cognitive function and irreversible neuronal loss. It is one of the primary diseases among elderly individuals. With an increasing incidence and a high failure rate for pharmaceutical options that are merely symptom-targeting and supportive with many side effects, there is an urgent need for alternative strategies. Despite extensive knowledge on the molecular basis of AD, progress concerning effective disease-modifying therapies has proven to be a challenge. The ability of the CRISPR-Cas9 gene editing system to help identify target molecules or to generate new preclinical disease models could shed light on the pathogenesis of AD and provide promising therapeutic possibilities. Here, we sought to highlight the current understanding of the involvement of the A673T mutation in amyloid pathology, focusing on its roles in protective mechanisms against AD, in relation to the recent status of available therapeutic editing tools.

Temporomandibular Joint Osteoarthritis: Pathogenic Mechanisms Involving the Cartilage and Subchondral Bone, and Potential Therapeutic Strategies for Joint Regeneration.

The temporomandibular joint (TMJ) is a specialized synovial joint that is crucial for the movement and function of the jaw. TMJ osteoarthritis (TMJ OA) is the result of disc dislocation, trauma, functional overburden, and developmental anomalies. TMJ OA affects all joint structures, including the articular cartilage, synovium, subchondral bone, capsule, ligaments, periarticular muscles, and sensory nerves that innervate the tissues. The present review aimed to illustrate the main pathomechanisms involving cartilage and bone changes in TMJ OA and some therapeutic options that have shown potential restorative properties regarding these joint structures in vivo. Chondrocyte loss, extracellular matrix (ECM) degradation, and subchondral bone remodeling are important factors in TMJ OA. The subchondral bone actively participates in TMJ OA through an abnormal bone remodeling initially characterized by a loss of bone mass, followed by reparative mechanisms that lead to stiffness and thickening of the condylar osteochondral interface. In recent years, such therapies as intraarticular platelet-rich plasma (PRP), hyaluronic acid (HA), and mesenchymal stem cell-based treatment (MSCs) have shown promising results with respect to the regeneration of joint structures or the protection against further damage in TMJ OA. Nevertheless, PRP and MSCs are more frequently associated with cartilage and/or bone repair than HA. According to recent findings, the latter could enhance the restorative potential of other therapies (PRP, MSCs) when used in combination, rather than repair TMJ structures by itself. TMJ OA is a complex disease in which degenerative changes in the cartilage and bone develop through intricate mechanisms. The regenerative potential of such therapies as PRP, MSCs, and HA regarding the cartilage and subchondral bone (alone or in various combinations) in TMJ OA remains a matter of further research, with studies sometimes obtaining discrepant results.

Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?

The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer's, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.