Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the leading cause of dementia and one of the most devastating neurodegenerative diseases. In the last decades, a large proportion of AD patients have been described as having aberrant accumulation of TDP-43 protein, a well-established driver of neurodegeneration. This TDP-43 proteinopathy in AD can co-occur in neurons with the main hallmarks of the disease, toxic amyloid oligomers and neurofibrillary tangles containing hyperphosphorylated Tau, and correlates with rapid progression and worse prognosis.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), the most common aging-associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP-43 as a secondary pathology. Clinically, AD patients with secondary TDP-43 pathology have more severe cognitive impairment, more rapid cognitive decline, worse brain atrophy, and a shorter disease course.

Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.

Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell.

Involvement of CB and CB receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice.

Background: The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model of frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated.

Methods: We have investigated the involvement of the CB and the CB receptor using chronic treatments with selective ligands in CaMKIIα-TDP-43 mice, analysis of their cognitive deterioration with the Novel Object Recognition test, and immunostaining for neuronal and glial markers in two areas of interest in frontotemporal dementia.

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominance and reveals potential modulating targets.

Alzheimer's disease (AD), the most common aging-associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP-43 as a secondary pathology. The presence of TDP-43 pathology in AD is associated with increased tau neuropathology and worsened clinical outcomes in AD patients.

Inactivation of the CB receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis.

The activation of the cannabinoid receptor type-2 (CB ) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB receptor knock-out mice to generate double mutants.

Targeting the CB receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis.

Cannabinoids form a singular group of plant-derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons.

Structure-Effect Relationships of Novel Semi-Synthetic Cannabinoid Derivatives.

As a library of cannabinoid (CB) derivatives with (-)--cannabidiol (CBD) or (-)--cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), -hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and -hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models. Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells.

Cannabidiol Administration Prevents Hypoxia-Ischemia-Induced Hypomyelination in Newborn Rats.

Neonatal hypoxia-ischemia (HI) is a risk factor for myelination disturbances, a key factor for cerebral palsy. Cannabidiol (CBD) protects neurons and glial cells after HI insult in newborn animals. We hereby aimed to study CBD's effects on long-lasting HI-induced myelination deficits in newborn rats.

Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1 transgenic mice, an experimental model of amyotrophic lateral sclerosis.

Antioxidant phytocannabinoids, synthetic compounds targeting the CB receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1 mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too. Here, we have investigated the neuroprotective effects in SOD1 mutant mice of the cannabigerol derivative VCE-003.

Targeting glial cannabinoid CB receptors to delay the progression of the pathological phenotype in TDP-43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis.

Background And Purpose: Cannabinoid CB receptors are up-regulated in reactive microglia in the spinal cord of TDP-43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up-regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB receptor function.

Experimental Approach: We treated TDP-43 (A315T) transgenic mice with the non-selective agonist WIN55,212-2, alone or combined with selective CB or CB antagonists, as well as with the selective CB agonist HU-308, and evaluated their effects on the pathological phenotype.

Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB receptor ligand antagonists.

A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB and CB receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB receptors (K values of 44.6 nM for CB receptors and >40 μM for CB receptors, respectively).