Dysfunction of striatal dopaminergic circuits has been implicated in motor impairment and Parkinson’s disease (PD)-related circadian perturbations that may represent an early prodromal marker of PD. Cyclin-dependent kinase 5 (CDK5) negatively regulates dopamine signaling in the striatum, suggesting a critical role of CDK5 in circadian and sleep disorders. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to produce mice with a dorsal striatum (DS)-specific knockdown (KD) of the Cdk5 gene (referred to as DS-CDK5-KD mice) and investigate its role in vivo. DS-CDK5-KD mice exhibited deficits in locomotor activity and disturbances in activity/rest behavior. Additionally, Golgi staining of neurons in the DS revealed that CDK5 deletion reduced dendrite length and the number of functional synapses, which was confirmed by significant downregulation of MAP2, PSD-95, and synapsin I. Correlated with this, DS-CDK5-KD mice displayed reduced phosphorylation of Tau at Thr181. Furthermore, whole-cell patch-clamp recordings of green fluorescent protein-tagged neurons in the striatum of DS-CDK5-KD mice revealed a decreased frequency of spontaneous inhibitory postsynaptic currents and altered excitatory/inhibitory synaptic balance. Notably, anterograde labeling showed that CDK5 KD in the DS disrupted long-range projections to the secondary motor cortex, dorsal and ventral thalamic nuclei, and basolateral amygdala, which are involved in the regulation of motor and circadian rhythms in the brain. These findings support a critical role of CDK5 in the DS in maintaining the striatal neural circuitry underlying motor functions and activity/rest associated with circadian rhythms that are perturbed in neurodegenerative disorders.

Hypoxic environments at high altitudes influence the long-term non-altitude health of residents, by inducing changes in metabolism and the mitochondria, severe lung injury, and endangering life. This study was aimed to determine whether meldonium can ameliorate hypoxia-induced lung injury and investigate its possible molecular mechanisms. We used Swiss mice and exposed type Ⅱ alveolar epithelial cell to hypobaric hypoxic conditions to induce lung injury and found that meldonium has significant preventive effect, which was associated with the regulation of glycolysis. We found using human proteome microarrays assay, molecular docking, immunofluorescence and pull-down assay that the target protein of meldonium is a platelet-type phosphofructokinase (PFKP), which is a rate-limiting enzyme of glycolysis. Also, meldonium promotes the transfer of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, which mitigates oxidative stress and mitochondrial damage under hypoxic condition. Mechanistically, meldonium ameliorates lung injury by targeting PFKP to regulate glycolysis, which promotes Nrf2 translocation from the cytoplasm to the nucleus to alleviate oxidative stress and mitochondrial damage under hypoxic condition. Our study provides a novel potential prevention and treatment strategy against hypoxia-induced lung injury.

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Objective: Meldonium, a well-known cardioprotective drug, has been reported to be protective against pulmonary injury at high altitudes; however, the pharmacodynamics of meldonium in other vital organs under acute high-altitude injury are less investigated and the related pharmacokinetics have not been fully elucidated.Methods and Results: The present study examined the basic pharmacodynamics and pharmacokinetics (PK) in rat exposure to acute high-altitude hypoxia after intragastrical and intravenous pre-administration of meldonium. The results indicate that meldonium can improve acute hypoxia-induced pathological damage in brain and lung tissues, and restore blood biochemistry and routine blood index of heart, liver and kidney tissues under a simulated acute high-altitude environment. Furthermore, compared to the normoxia group, rats exposed to simulated high-altitude hypoxia and premedicated with intragastrical meldonium showed linear kinetics in the dose range of 25–100 mg/kg, with a significantly increase in the area under curve (AUC) and reduced clearance rate. No significant differences in these meldonium of PK parameters were observed with intravenous administration. Additionally, meldonium was involved in the regulation of succinic acid and 3-hydroxypropionic acid.Conclusion: These results will contribute to our understanding of the preclinical PK properties of meldonium and its acute high-altitude protective effects.