Category Archives: Alzheimer’s Disease (AD)

Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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“Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3-4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.”

https://pubmed.ncbi.nlm.nih.gov/37534036/

“Our findings imply that the THC microdose treatment alleviates age-dependent cognitive deficits by modulating multiple hallmarks of brain aging, supporting past hypotheses regarding the relation between aging and the endocannabinoid system.”

https://www.frontiersin.org/articles/10.3389/fnins.2023.1182932/full

The role of cannabidiol in aging

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“Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.”

https://pubmed.ncbi.nlm.nih.gov/37418976/

“CBD is a potential antiaging candidate. CBD possesses antioxidant, anti-inflammatory and autophagy-inducing properties. CBD has potentially beneficial therapeutic effects for several age-related diseases.”

https://www.sciencedirect.com/science/article/pii/S075333222300865X?via%3Dihub


Under the umbrella of depression and Alzheimer’s disease physiopathology: can cannabinoids be a dual-pleiotropic therapy?

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“Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60% to 80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises.

Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aβ) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids.

At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.”

https://pubmed.ncbi.nlm.nih.gov/37414155/

“Endocannabinoid system is dysregulated in depression and AD.

Cannabinoids have potential to modulate the physiopathological mechanisms common in both diseases.”

https://www.sciencedirect.com/science/article/pii/S1568163723001575?via%3Dihub


Cannabis sativa-based oils against aluminum-induced neurotoxicity

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“The use of terpenoid compounds in different neural-related conditions is becoming useful for several illnesses. Another possible activity of these compounds is the reduction of nervous impairment. Cannabis sativa plants are known for their concentration of two important terpenoids, the delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD and THC have central peripheral activities already described and their usage in different brain diseases, such as Alzheimer’s and multiple sclerosis. Aluminum (Al) is known as an important neurotoxic compound, the physiological action of Al is not known already, and in high concentrations can lead to intoxication and cause neurotoxicity. Here we evaluated the potential effect of two different doses of CBD- and THC-rich based oils against Al-induced toxicity, in the zebrafish model. We evaluated behavioral biomarkers of the novel tank test (NTT) and social preference test (SPT), and biochemical markers: the activity of the enzyme acetylcholinesterase (AChE) and the antioxidant enzymes-catalase, superoxide dismutase, and glutathione-S-transferase. CBD- and THC-based oils were able to increase the AChE activity helping the cholinergic nervous system actuate against Al toxicity which was reflected by the behavioral biomarkers changes. We concluded that the oils have a protective effect and might be used with proposals for neurological and antioxidant impairment avoidance caused by Al intoxications.”

https://pubmed.ncbi.nlm.nih.gov/37330587/

“In our study, we observed that Al is responsible for neurotoxicity, especially causing AChE decrease. The main effect of Al is related to reduced social ability and anxiety-like patterns. The testes oil THC- and CBD-rich have an important role in AChE reestablishment and social ability reacquisition. In addition, both oils exert an outstanding effect on antioxidant enzyme modulations with the re-establishment of the SOD and CTL after Al exposition. The activity of GST was also well modulated indicating that the oils played a crucial role in cellular damage avoidance. However, the oils do not change the impaired anxiety-like behavior that looks to be linked to other central signaling pathways and needs to be well investigated in the next studies. Finally, the oils have a protective effect and might be used with proposals for neurological and antioxidant impairment avoidance.”

https://www.nature.com/articles/s41598-023-36966-9

Examining the use of cannabidiol and delta-9-tetrahydrocannabinol-based medicine among individuals diagnosed with dementia living within residential aged care facilities: Results of a double-blind randomised crossover trial

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“Objective: Dementia affects individuals older than 65 years. Currently, residential aged care facilities (RACF) use psychotropic medications to manage behavioural and neuropsychiatric symptoms of dementia (BPSD), which are recommended for short-term use and have substantial side effects, including increased mortality. Cannabinoid-based medicines (CBM) have some benefits that inhibit BPSD and cause minimal adverse effects (AEs), yet limited research has been considered with this population. The study aimed to determine a tolerable CBM dose (3:2 delta-9-tetrahydrocannabinol:cannabidiol), and assessed its effect on BPSD, quality of life (QoL) and perceived pain.

Methods: An 18-week randomised, double-blinded, crossover trial was conducted. Four surveys, collected on seven occasions, were used to measure changes in BPSD, QoL and pain. Qualitative data helped to understand attitudes towards CBM. General linear mixed models were used in the analysis, and the qualitative data were synthesised.

Results: Twenty-one participants (77% female participants, mean age 85) took part in the trial. No significant differences were seen between the placebo and CBM for behaviour, QOL or pain, except a decrease in agitation at the end of treatment in favour of CBM. The qualitative findings suggested improved relaxation and sleep among some individuals. Post hoc estimates on the data collected suggested that 50 cases would draw stronger conclusions on the Neuropsychiatric Inventory.

Conclusions: The study design was robust, rigorous and informed by RACF. The medication appeared safe, with minimal AEs experienced with CBM. Further studies incorporating larger samples when considering CBM would allow researchers to investigate the sensitivity of detecting BPSD changes within the complexity of the disease and concomitant with medications.”

https://pubmed.ncbi.nlm.nih.gov/37321847/

https://onlinelibrary.wiley.com/doi/10.1111/ajag.13224

Therapeutic use of cannabinoids for the treatment of neurodegenerative disorders: a potential breakthrough

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“Marijuana, also known as cannabis, is a plant-based illicit drug notorious for its recreational purposes. However, in recent years its extracts are being extensively studied for their overall therapeutic effects. Active substances found in marijuana that interact with the endocannabinoid system are known as cannabinoids, the primary examples being 9-tetrahydrocannabinol (9-THC) and Cannabidiol (CBD). These cannabinoids ligand to receptors such as CB1 (found in CNS) and CB2 (found in immune system cells) to prevent the release of neurotransmitters and modulate immune cell migration as well as cytokine release, respectively (1). In recent years, there has been a surge of interest in the neuroprotective potential of marijuana; however, investigators could not make firm conclusions about the effectiveness of these treatments. A comprehensive review by Bahji A et al. (2022) found an evident link between cannabidiol-based products and relief from the motor as well as behavioural and psychological symptoms spanning Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) (2). Here we discuss the effects of marijuana and its derivatives on the treating significant neurodegenerative disorders.

Dronabinol (2.5 mg) seemed to lessen the disordered behaviours as assessed by the Cohen-Mansfield Agitation Inventory in 12 patients of AD (p=0.05) (3). Sherman et al. (2018) reported the association of cannabis administration with weight and pain management in AD patients. The adverse effects are typically well tolerated at the levels supplied, even though cannabis is linked to an increased risk of euphoria, sleepiness and psychosis (1). On the other hand, for HD, nabilone (1 or 2 mg) had a substantial therapeutic benefit in a different 10-week placebo-controlled crossover experiment as determined by the overall motor and chorea score on the Unified Huntington’s Disease Rating Scale (UHDRS) (4). Available reviews revealed variable evidence suggesting the clinical benefits of cannabis in treating motor symptoms in patients with PD. A randomized trial found that compared to a placebo, giving a single dosage of 300 mg of CBD successfully decreased tremor amplitude (5).

Neurological diseases, including  the  neurodegenerative diseases,  comprise  8.7% of the disease burden  in lower- middle- income countries (such as Pakistan) (6). Currently, there is no real cure for neurodegenerative disorders, only symptomatic management, such as dopamine treatment for PD or cholinesterase inhibitors for dementia. Cannabinoids might be the lifeline all neurodegenerative disorder patients have been waiting for.”

https://pubmed.ncbi.nlm.nih.gov/37218269/

https://ojs.jpma.org.pk/index.php/public_html/article/view/7805

Phytocannabinoids as Potential Multitargeting Neuroprotectants in Alzheimer’s Disease

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“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.”

https://pubmed.ncbi.nlm.nih.gov/37132109/

https://www.eurekaselect.com/article/131371

Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

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“Alzheimer’s disease (AD) represents the most common form of dementia, characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, the accumulation of misfolded protein, ER stress and neuronal apoptosis. It is of main importance to find new therapeutic strategies because AD prevalence is increasing worldwide.

Cannabinoids are arising as promising neuroprotective phytocompounds. In this study, we evaluated the neuroprotective potential of Δ8-THC pretreatment in an in vitro model of AD through transcriptomic analysis.

We found that Δ8-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Aβ1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase in Bax and the decrease in Bcl-2 both at gene and protein expression levels. Moreover, genes involved in protein folding and degradation were also deregulated. On the contrary, Δ8-THC pretreatment reduced ER stress and, as a consequence, neuronal apoptosis.

Then, the results demonstrated that Δ8-THC might represent a new neuroprotective agent in AD.”

https://pubmed.ncbi.nlm.nih.gov/37047608/

“The results suggested that Δ8-THC may represent a novel neuroprotective agent in AD but also in other neurodegenerative diseases characterized by the accumulation of misfolded proteins.”

https://www.mdpi.com/1422-0067/24/7/6598

The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer’s Disease-like Mouse Model

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“Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA.

In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system.

The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer’s disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ1-42-treated mouse model. We observed that Aβ1-42-treated mice had more hippocampal Aβ and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aβ and p-tau and superior cognitive function compared with Aβ1-42-treated mice. In addition, CBDA and THCA lowered Aβ and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons.

Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aβ, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.”

https://pubmed.ncbi.nlm.nih.gov/37047798/

https://www.mdpi.com/1422-0067/24/7/6827

Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease

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“Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer’s disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD.

Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.04, 0.008, and 0.02 mg/kg, respectively, once daily for 3 months. The spatial memory of the mice was assessed using the radial arm water maze (RAWM) test before and after drug treatment. Brain tissues were collected at the end of the treatment period for the assessment of Aβ load, tauopathy state, and markers of mitochondrial function.

The RAWM test revealed that the treatment with the melatonin-insulin-THC (MIT) nasal spray improved the spatial learning memory of APP/PS1 mice significantly. Results of protein analyses of brain homogenates indicated that MIT treatment significantly decreased the tau phosphorylation implicated in tau toxicity (p < 0.05) and the expression of CKMT1 associated with mitochondrial dysfunction. Moreover, MIT significantly decreased the expression of two mitochondrial fusion-related proteins, Mfn2 and Opa1 (p < 0.01 for both), while increasing the expression of a mitophagy regulator, Parkin, suggesting a compensatory enhancement of mitophagy due to MIT-promoted mitochondrial fusion.

In conclusion, this study was the first to demonstrate the ability of an MIT nanoformulation to improve spatial memory in AD mice through its multi-targeting effects on Aβ production, tau phosphorylation, and mitochondrial dynamics. Thus, MIT may be a safe and effective therapeutic for AD.”

https://pubmed.ncbi.nlm.nih.gov/36830601/

“The results of the present study provide the first evidence that MIT nanoformulation containing melatonin, insulin, and THC has potential as a multi-targeting treatment for AD.”

https://www.mdpi.com/2218-273X/13/2/232