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Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission. [ABSTRACT FROM AUTHOR]

Research on bioactive compounds has grown recently due to their health benefits and limited adverse effects, particularly in reducing the risk of chronic diseases, including neurodegenerative conditions. According to these observations, this study investigates the activity of sulforaphane (RS-GRA) on an in vitro model of differentiated NSC-34 cells. We performed a transcriptomic analysis at various time points (24 h, 48 h, and 72 h) and RS-GRA concentrations (1 µM, 5 µM, and 10 µM) to identify molecular pathways influenced by this compound and the effects of dosage and prolonged exposure. We found 39 differentially expressed genes consistently up- or downregulated across all conditions. Notably, Nfe2l2, Slc1a5, Slc7a11, Slc6a9, Slc6a5, Sod1, and Sod2 genes were consistently upregulated, while Ripk1, Glul, Ripk3, and Mlkl genes were downregulated. Pathway perturbation analysis showed that the overall dysregulation of these genes results in a significant increase in redox pathway activity (adjusted p-value 1.11 × 10−3) and a significant inhibition of the necroptosis pathway (adjusted p-value 4.64 × 10−3). These findings suggest RS-GRA's potential as an adjuvant in neurodegenerative disease treatment, as both increased redox activity and necroptosis inhibition may be beneficial in this context. Furthermore, our data suggest two possible administration strategies, namely an acute approach with higher dosages and a chronic approach with lower dosages. [ABSTRACT FROM AUTHOR]

Oxidative stress is a common feature of neurodegenerative diseases. Different natural compounds mediate neuroprotective effects by activating the Nrf2 antioxidant response. Some isothiocyanates are Nrf2 activators, including Moringin (MOR). In this study, the transcriptional profile of differentiated NSC-34 motor neurons was evaluated after treatment for 48 h and 96 h with concentrations of 0.5, 5, and 10 µM of a new MOR formulation obtained with α-cyclodextrin (α-CD). All the concentrations increased gene expression and cytoplasmic protein levels of Nrf2 at 96 h. However, the highest dose also increased nuclear Nrf2 levels at 96 h. Then, Nrf2 interactors were selected using STRING, and common biological process (BP) terms between the groups were evaluated. α-CD/MOR was able to modulate BP related to responses to oxidative stress, proteostasis, and autophagy. Specifically, the treatment with 10 µM of α-CD/MOR for 96 h induced genes involved in glutathione synthesis and proteasome subunits and reduced the expression of genes related to endoplasmic reticulum stress. Moreover, this group showed the lowest levels of the apoptotic markers Bax, cleaved caspase 9, and cleaved caspase 3. These results indicate the beneficial effects of prolonged α-CD/MOR supplementation that are mediated, at least in part, by Nrf2 activation. Then, α-CD/MOR could be a valuable treatment against neurodegenerative diseases, in particular motor neuron degeneration. [ABSTRACT FROM AUTHOR]

Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects. In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes. Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of Cdkn2a, Cdkn2c and Cdkn2d genes, which are known to suppress the cell cycle. Ccne2, Cdk2, Cdk7, Anapc11, Anapc10, Cdc23, Cdc16, Anapc4, Cdc27, Stag1, Smc3, Smc1a, Nipbl, Pds5a, Pds5b, and Wapl genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disorder. AD hallmarks are extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. It is interesting to notice that Aβ plaques appear in the cerebellum only in late stages of the disease, and then it was hypothesized that it can be resistant to specific neurodegenerative mechanisms. However, the role of cerebellum in AD pathogenesis is not clear yet. In this study, we performed an in silico analysis to evaluate the transcriptional profile of cerebellum in AD patients and non-AD subjects in order to deepen the knowledge on its role in AD. The analysis evidenced that only the molecular function (MF) "active ion transmembrane transporter activity" was overrepresented. Regarding the 21 differentially expressed genes included in this MF, some of them may be involved in the ion dyshomeostasis reported in AD, while others assumed, in the cerebellum, an opposite regulation compared to those reported in other brain regions in AD patients. They might be associated to a protective phenotype, that may explain the initial resistance of cerebellum to neurodegeneration in AD. Of note, this MF was not overrepresented in prefrontal cortex and visual cortex indicating that it is a peculiarity of the cerebellum. [ABSTRACT FROM AUTHOR]

Neuronal cell death is a physiological process that, when uncontrollable, leads to neurodegenerative disorders like spinal cord injury (SCI). SCI represents one of the major causes of trauma and disabilities worldwide for which no effective pharmacological intervention exists. Herein, we observed the beneficial effects of Δ8-Tetrahydrocannabinol (Δ8-THC) during neuronal cell death recovery. We cultured NSC-34 motoneuron cell line performing three different experiments. A traumatic scratch injury was caused in two experiments. One of the scratched was pretreated with Δ8-THC to observe the role of the cannabinoid following the trauma. An experimental control group was neither scratched nor pretreated. All the experiments underwent RNA-seq analysis. The effects of traumatic injury were observed in scratch against control comparison. Comparison of scratch models with or without pretreatment highlighted how Δ8-THC counteracts the traumatic event. Our results shown that Δ8-THC triggers the cytoskeletal remodeling probably due to the activation of the Janus Kinase Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway and the signaling cascade operated by the Mitogen-Activated Protein (MAP) Kinase signaling pathway. In light of this evidence, Δ8-THC could be a valid pharmacological approach in the treatment of abnormal neuronal cell death occurring in motoneuron cells. [ABSTRACT FROM AUTHOR]

Cannabinoids, natural or synthetic, have antidepressant, anxiolytic, anticonvulsant, and anti-psychotic properties. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied cannabinoids, but recently, attention has turned towards minor cannabinoids. Delta-8-tetrahydrocannabinol (Δ8-THC), an isomer of Δ9-THC, is a compound for which, to date, there is no evidence of its role in the modulation of synaptic pathways. The aim of our work was to evaluate the effects of Δ8-THC on differentiated SH-SY5Y human neuroblastoma cells. Using next generation sequencing (NGS), we investigated whether Δ8-THC could modify the transcriptomic profile of genes involved in synapse functions. Our results showed that Δ8-THC upregulates the expression of genes involved in the glutamatergic pathway and inhibits gene expression at cholinergic synapses. Conversely, Δ8-THC did not modify the transcriptomic profile of genes involved in the GABAergic and dopaminergic pathways. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]