“Dementia includes a variety of neurodegenerative diseases that affect and target the brain’s fundamental cognitive functions. It is undoubtedly one of the diseases that affects people globally. The ameliorating the disease is still not known; the symptoms, however, can be prevented to an extent. Dementia encompasses Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lewy body dementia, mixed dementia, and various other diseases.
The aggregation of β-amyloid protein plaques and the formation of neurofibrillary tangles have been concluded as the foremost cause for the onset of the disease. As the cases climb, new neuroprotective methods are being developed in the form of new drug delivery systems that provide targeted delivery.
Herbal drugs like Ashwagandha, Brahmi, and Cannabis have shown satisfactory results by not only treating the symptoms but have also been shown to reduce and ameliorate the formation of amyloid plaque formation.
This article explores the intricate possibilities of drug delivery and the absolute use of herbal drugs to target neurodegenerative diseases. The various possibilities of nanotechnology currently available with new emerging techniques are also discussed.”
“Alzheimer’s disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis.
Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment.
Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model.
Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the “Alzheimer’s disease-amyloid secretase pathway”. Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis.
These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model.”
“In conclusion, we documented for the first time that a cannabinoid, CBNR, is able to regulate AS in an in vitro AD model. CBNR pre-treatment restored the splicing defects produced by Aβ exposure, involving genes also highly associated with AD. Moreover, thanks to this mechanism, CBNR probably counteracts the Aβ-induced mis-regulation of genes, due to premature stop codons and miRNA or lncRNA targeting. This work improves our knowledge of the molecular mechanisms that can be potentially useful in treating AD, corroborating the fact that drugs targeting post-transcriptional splicing processes could be considered novel and valid choices in neuroprotection and prevention issues.”
“Background: Alzheimer’s disease (AD) is a prevalent, incurable, and chronic neurodegenerative condition characterized by the accumulation of amyloid-β protein (Aβ), disrupting various bodily systems. Despite the lack of a cure, phenolic compounds like cannabidiol (CBD), a non-psychoactive component of cannabis, have emerged as potential therapeutic agents for AD.
Objective: This systematic review explores the impact of different types of cannabidiol on AD, unveiling their neuroprotective mechanisms.
Methods: The research used PubMed, Scopus, and Web of Science databases with keywords like “Alzheimer’s disease” and “Cannabidiol.” Studies were evaluated based on title, abstract, and relevance to treating AD with CBD. No restrictions on research type or publication year. Excluded were hypothesis papers, reviews, books, unavailable articles, etc.
Results: Microsoft Excel identified 551 articles, with 92 included in the study, but only 22 were thoroughly evaluated. In-vivo and in-silico studies indicate that CBD may disrupt Aβ42, reduce pro-inflammatory molecule release, prevent reactive oxygen species formation, inhibit lipid oxidation, and counteract Aβ-induced increases in intracellular calcium, thereby protecting neurons from apoptosis.
Conclusions: In summary, the study indicates that CBD and its analogs reduce the production of Aβ42. Overall, these findings support the potential of CBD in alleviating the underlying pathology and symptoms associated with AD, underscoring the crucial need for further rigorous scientific investigation to elucidate the therapeutic applications and mechanisms of CBD in AD.”
“In conclusion, the finding of this study indicates that cannabidiol/derivatives inhibit AD progression through various mechanisms and key hypotheses regarding AD pathology. Nave CBD can reduce Aβ, IL-6 expression in peripheral leukocytes, and retarded cognitive decline. Compare with other CBD derivatives, CBD carbamate derivatives notably reduced Aβ1–42 levels, restored cognitive function to a normal state, and exhibited superior behavioral performance when compared to donepezil. CBD decreases Caspase 9, Caspase 3, and cleaved PARP1 protein levels and shows Antiapoptotic effects during cognitive decline. It also shows anti-cholinergic activity by inhibiting AChE and BuChE. As a result, the expression of ChAT can be normalized. In terms of the neuroinflammatory process, the expression of proinflammatory miRNAs (miR-146a, miR-155, and miR-34a) associated with TLR and NF-κB signaling is reduce. Therefore, continued research efforts should focus on elucidating the precise mechanisms of action, exploring potential synergies with other AD medications, and optimizing CBD formulations and derivatization to maximize therapeutic benefits in AD patients. These observations underscore the significance of further research and exploration into the therapeutic applications of CBD in the context of AD.”
“Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and behavior impairments. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease modifying and easily accessible therapies. Emerging evidence suggests that targeting the endocannabinoid system may hold promise for AD therapy as it plays a crucial role in different physiological processes, including learning, memory and anxiety, as well as inflammatory and immune responses.
Objective: In this study, we investigated the therapeutic potential of the synthetic cannabinoid WIN 55,212-2 on memory deficits in Tg4-42 transgenic mice.
Methods: Tg4-42 mice were assigned to two treatment groups to investigate the preventive effects of WIN 55,212-2 after a prolonged washout period, as well as the therapeutic effects of WIN 55,212-2 on behavior. Furthermore, the effects of WIN 55,212-2 treatment on AD pathology, including inflammation, amyloid-β load, neurogenesis, and brain glucose metabolism, were evaluated.
Results: Therapeutic WIN 55,212-2 treatment rescued recognition memory and spatial reference deficits in Tg4-42 mice. Furthermore, therapeutic WIN 55,212-2 administration improved motor performance. In addition, preventative WIN 55,212-2 treatment rescued spatial learning and reference memory deficits. Importantly, WIN 55,212-2 treatment did not affect anxiety-like behavior. However, therapeutic and preventative WIN 55,212-2 treatment resulted in an increase locomotor activity and swimming speed in Tg4-42 mice. WIN-treatment reduced microgliosis in the hippocampus of preventively treated mice and rescued brain glucose metabolism in therapeutically treated Tg4-42 mice.
Conclusions: Our findings emphasize the therapeutic promise of the synthetic cannabinoid WIN 55,212-2 in alleviating behavioral and cognitive deficits linked to AD.”
“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC)”
“Rationale: With increasing legalization of recreational and medical cannabis, use of this drug is growing rapidly among older adults. As cannabis can impair cognition in young adults, it is critically important to understand how its consumption interacts with the cognitive profile of aged subjects, who are already at increased risk of decline.
Objectives: The current study was designed to determine how cannabis influences multiple forms of cognition in young adult and aged rats of both sexes when delivered via two translationally-relevant routes of administration.
Methods: Rats were exposed acutely to cannabis smoke or chronically to oral Δ9-tetrahydrocannabinol (Δ9THC), followed by cognitive testing.
Results: Acute cannabis smoke enhanced prefrontal cortex-dependent working memory accuracy in aged males, but impaired accuracy in aged females, while having no effects in young adults of either sex. In contrast, the same cannabis smoke regimen had minimal effects on a hippocampus-dependent trial-unique non-matching to location mnemonic task, irrespective of age or sex. Chronic oral consumption of Δ9THC enhanced working memory in aged rats of both sexes, while having no effects in young adults. In contrast, the same Δ9THC regimen did not affect spatial learning and memory in either age group. Minimal age differences were observed in Δ9THC pharmacokinetics with either route of administration.
Conclusions: The results show that cannabis and Δ9THC can attenuate working memory impairments that emerge in aging. While these enhancing effects do not extend to hippocampus-dependent cognition, cannabis does not appear to exacerbate age-associated impairments in this cognitive domain.”
“Agitation is a common complication of Alzheimer’s dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD.
We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD.
Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described.
Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.”
“Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain’s immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration into the central nervous system.
Medicinal plants, with their historical use in traditional medicine, have emerged as promising candidates to mitigate neuroinflammation and offer a sustainable alternative for addressing neurodegenerative conditions in a green healthcare framework.
This review evaluates the effects of medicinal plants on neuroinflammation, emphasizing their mechanisms of action, effective dosages, and clinical implications, based on a systematic search of databases such as PubMed, SCOPUS, and Web of Science.
The key findings highlight that plants like Cleistocalyx nervosum var. paniala, Curcuma longa,
Cannabis sativa,
and Dioscorea nipponica reduce pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), inhibit enzymes (COX-2 and iNOS), and activate antioxidant pathways, particularly Nrf2. NF-κB emerged as the primary pro-inflammatory pathway inhibited across studies. While the anti-inflammatory potential of these plants is significant, the variability in dosages and phytochemical compositions limits clinical translation.
Here, we highlight that medicinal plants are effective modulators of neuroinflammation, underscoring their therapeutic potential. Future research should focus on animal models, standardized protocols, and safety assessments, integrating advanced methodologies, such as genetic studies and nanotechnology, to enhance their applicability in neurodegenerative disease management.”
“Addressing neuroinflammation to reduce disease severity and improve patient outcomes is a promising strategy against neurodegeneration. From a molecular perspective, there are several conventional drug targets for neuroinflammation, such as enzymes, receptors, and ion channels. However, the high cost of synthetic drugs presents a challenge, emphasizing the need for alternative approaches. This has heightened interest in naturally occurring medicinal plants known for their antioxidant, anti-inflammatory, and neuroprotective properties. These plants are often more cost-effective and have been safely utilized in treatments for thousands of year.”
“Cannabidiol (CBD), the primary non-intoxicating compound in cannabis, is currently approved for treating rare, treatment-resistant seizures.
Recent preclinical research suggests that CBD’s multifaceted mechanisms of action in the brain, which involve multiple molecular targets, underlie its neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic effects. Clinical trials are also exploring CBD’s therapeutic potential beyond its current uses.
This review focuses on CBD’s polypharmacological profile and discusses the latest preclinical and clinical findings regarding its efficacy in neuropsychiatric disorders.
Existing evidence suggests that CBD’s ability to modulate multiple signaling pathways may benefit neuropsychiatric disorders, and we propose further research areas to clarify its mechanisms, address data gaps, and refine its therapeutic indications.”
“Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability.
Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signaling.
Activation of the 5-HT2A intracellular signaling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket.
Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.”
“Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer’s disease psychosis: A systematic review and meta-analysis. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.”
“Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear.
Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG).
Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD.
These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.”
