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Background and Purpose: Therapeutic hypothermia (TH) has become the standard care to reduce morbidity and mortality in neonates affected by moderate‐to‐severe hypoxic–ischaemic encephalopathy (HIE). Despite the use of TH for HIE, the incidence of mortality and disabilities remains high. Experimental Approach: Nerve growth factor (NGF) is a potent neurotrophin, but clinical use is limited by its pain eliciting effects. CHF6467 is a recombinant modified form of human NGF devoid of algogenic activity (painless NGF). Key Results: In rodent hippocampal slices exposed to oxygen and glucose deprivation, CHF6467 protected neurons from death and reverted neurotransmission impairment when combined with hypothermia. In a model of rat neonatal HIE, intranasal CHF6467 (20 μg kg−1) significantly reduced brain infarct volume versus vehicle when delivered 10 min or 3 h after the insult. CHF6467 (20 and 40 μg kg−1, i.n.), significantly decreased brain infarct volume to a similar extent to TH and when combined, showed a synergistic neuroprotective effect. CHF6467 (20 μg kg−1, i.n.) per se and in combination with hypothermia reversed locomotor coordination impairment (Rotarod test) and memory deficits (Y‐maze and novel object recognition test) in the neonatal HIE rat model. Intranasal administration of CHF6467 resulted in meaningful concentrations in the brain, blunted HIE‐induced mRNA elevation of brain neuroinflammatory markers and, when combined to TH, significantly counteracted the increase in plasma levels of neurofilament light chain, a peripheral marker of neuroaxonal damage. Conclusion and Implications: CHF6467 administered intranasally is a promising therapy, in combination with TH, for the treatment of HIE. [ABSTRACT FROM AUTHOR]

Cannabis contains over 500 different compounds, including cannabinoids, terpenoids, and flavonoids. Cannabidiol (CBD) is a non-psychoactive constituent, whereas beta-caryophyllene (BCP) is one of most the well-known terpenoids of Cannabis sativa. In recent years, there has been an emerging idea that the beneficial activities of these compounds are greater when they are combined. The aim of this study was to evaluate the anti-inflammatory effect of CBD and BCP using the in vitro model of lipopolysaccharide (LPS)-stimulated human keratinocytes (HaCaT) cells. The vitality of the cells was quantified using LDH and MTT assays. The levels of the following pro-inflammatory proteins and genes were quantified: IL-1β, COX-2, and phospho-NF-κB p65 (p-p65) through Western blotting (WB) and interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) through quantitative real-time polymerase chain reaction (RT-qPCR). When present in the incubation medium, CBD and BCP reduced the increased levels of pro-inflammatory proteins (IL-1β, COX-2, and p-NF-kB) induced by LPS. The anti-inflammatory effects of CBD were blocked by a PPARγ antagonist, whereas a CB2 antagonist was able to revert the effects of BCP. Selected concentrations of CBD and BCP were able to revert the increases in the expression of pro-inflammatory genes (IL-1β, IL-6, and TNFα), and these effects were significant when the drugs were used in combination. Our results suggest that CBD and BCP work in concert to produce a major anti-inflammatory effect with good safety profiles. [ABSTRACT FROM AUTHOR]

The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of seven phytocannabinoids and four terpenes were considered. On the side of ligand‐based virtual screening, physico‐chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug‐like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure‐based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (−9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted. Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptors of the m[Glu.sub.1] and M[Glu.sub.5] subtypes exhibit a high degree of sequence homology and are both coupled to phospholipase C and intracellular [Ca.sup.2+] mobilization. However, functional differences have been detected for these receptor subtypes when they are coexpressed in the same neuronal populations. Experimental evidence indicates that m[Glu.sub.1] and m[Glu.sub.5] receptors play a differential role in models of cerebral ischemia and that only m[Glu.sub.1] receptors are implicated in the pathways leading to postischemic neuronal injury. The localization of m[Glu.sub.1] receptors in GABA-containing interneurons rather than in hippocampal CA1 pyramidal cells that are vulnerable to ischemia has prompted studies that have provided a new viewpoint on the neuroprotective mechanism of m[Glu.sub.1] receptor antagonists. The hypothesis predicts that these pharmacological agents attenuate post-ischemic injury by enhancing GABA-mediated neurotransmission.