Table 5.

Main results from the studies with non-selective agonists of CB₁R and CB₂R associated with cholinergic pathways and molecules that act through pathways related to the ECS.

Reference	Cannabinoid	Dosage	Major Results	Model Used
Non-selective agonists of CB1R and CB2R associated with cholinergic pathways
Nuñez-Borque et al., 2020 [93]	NP137	2.5 μΜ 5 μΜ 1 mg/kg/day p.o.	In vitro ↓ Aβ-induced cell death Inhibition of BChE (NP137) and BACE-1/BChE ↓ AD cell proliferative activity, ERK1/2 phosphorylation, AD lymphoblast p21 content In vivo ↓ Escape latency (MWM test) and restoration of cognitive functions (NP137)	In vitro experiments in immortalized lymphocytes of patients with delayed AD and in vivo experiments in TgAPP mice
	NP148	5 μΜ
Modulator molecules that act through pathways related to the endocannabinoid system
Balleza-Tapia et al., 2018 [94]	Capsaicin (Trpv-1 agonist)	10 μΜ	Prevention of nerve cell decline Resynchronization of emission of energy potentials in CA3 pyramidal cells Restoration of the balance between excitatory/inhibitory potentials	In vitro experiments in Aβ-treated hippocampal cells
Xiang et al., 2022a [96]	O-1602 (GPR-55 agonist)	2 μg/mouse 4 μg/mouse i.c.v.	↑ Cognitive functions (MWM, NOR tests) ↓ sAβ1–42 in hippocampus and frontal cortex ↓ RhoA, ROCK2 Reverse of GPR-55 downregulation ↓ MDA, ↑ GSH, SOD, CAT	In vivo experiments in Aβ1–42-treated mice
Xiang et al., 2022b [98]			Improvement in synaptic function (upregulation of PSD-95) ↓ Pro-inflammatory cytokines, microglial activation Prevention of AChE upregulation	In vivo experiments in STZ-treated mice
Wang et al., 2022 [99]			Prevention of hippocampal cell apoptosis (TUNEL staining) ↓ Expression of NF-κB p65, Bax ↓ Caspase-3 activity ↑ Expression of Bcl-2, anti-inflammatory cytokines	In vivo experiments in LPS-treated mice

Abbreviations: Aβ: amyloid beta; AChE: acetylcholinesterase; AD: Alzheimer’s disease; BACE-1: β-site amyloid precursor protein cleaving enzyme; Bax: Bcl-2-associated X protein; BChE: butyrylcholinesterase; Bcl-2: B cell leukemia/lymphoma 2 protein; CAT: catalase; ERK1/2: extracellular signal-regulated kinase 1/2; GPR-55: G-protein coupled receptor 55; GSH: glutathione; i.c.v.: intracerebroventricular; LPS: lipopolysaccharide; MDA: malondialdehyde; MWM: Morris water maze; NF-κB: nuclear factor-κB; NOR: novel object recognition; p.o.: per os; PSD-95: postsynaptic density protein 95; RhoA: Ras homolog family member A; ROCK2: Rho-associated coiled-coil-containing protein kinase 2; SOD: superoxide dismutase; STZ: streptozotocin; Trpv-1: transient receptor potential cation channel subfamily V member 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling.