In Vitro and In Vivo Anti-Inflammatory and Antidepressant-like Effects of Cannabis sativa L. Extracts.

Cannabis sativa L. has been widely used by humans for centuries for various purposes, such as industrial, ceremonial, medicinal, and food. The bioactive components of Cannabis sativa L. can be classified into two main groups: cannabinoids and terpenes. These bioactive components of Cannabis sativa L. leaf and inflorescence extracts were analyzed. Mice were systemically administered 30 mg/kg of Cannabis sativa L. leaf extract 1 h before lipopolysaccharide (LPS) administration, and behavioral tests were performed. We conducted an investigation into the oxygen saturation, oxygen tension, and degranulation of mast cells (MCs) in the deep cervical lymph nodes (DCLNs). To evaluate the anti-inflammatory effect of Cannabis sativa L. extracts in BV2 microglial cells, we assessed nitrite production and the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. The main bioactive components of the Cannabis sativa L. extracts were THCA (a cannabinoid) and ß-caryophyllene (a terpene). Cannabis sativa L. leaf extract reduced the immobility time in the forced swimming test and increased sucrose preference in the LPS model, without affecting the total distance and time in the center in the open field test. Additionally, Cannabis sativa L. leaf extract improved oxygen levels and inhibited the degranulation of MCs in DCLNs. The Cannabis sativa L. extracts inhibited IL-1ß, IL-6, TNF-α, nitrite, iNOS, and COX-2 expression in BV2 microglia cells. The efficacy of Cannabis sativa L. extracts was suggested to be due to the entourage effect of various bioactive phytochemicals. Our findings indicate that these extracts have the potential to be used as effective treatments for a variety of diseases associated with acute inflammatory responses.

Development of 18F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson's Disease.

Activated Abelson non-receptor tyrosine kinase (c-Abl) plays a harmful role in neurodegenerative conditions such as Parkinson's disease (PD). Inhibition of c-Abl is reported to have a neuroprotective effect and be a promising therapeutic strategy for PD. We have previously identified a series of benzo[d]thiazole derivatives as selective c-Abl inhibitors from which one compound showed high therapeutic potential. Herein, we report the development of a complementary positron emission tomography (PET) tracer. In total, three PET tracer candidates were developed and eventually radiolabeled with fluorine-18 for in vivo evaluation studies in mice. Candidate [18F]3 was identified as the most promising compound, since it showed sufficient brain uptake, good washout kinetics, and satisfactory metabolic stability. In conclusion, we believe this tracer provides a good starting point to further validate and explore c-Abl as a target for therapeutic strategies against PD supported by PET.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

Nrf2 activator via interference of Nrf2-Keap1 interaction has antioxidant and anti-inflammatory properties in Parkinson's disease animal model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.