ZLN005

Parkinson's disease (PD) is a neurodegenerative condition marked by significant motor impairments, resulting from extensive loss of dopaminergic neurons and abnormal protein aggregation. One of the early features of PD is disrupted mitochondrial dynamics, which arises from imbalances in cellular energy regulation. Therapeutic strategies that mitigate the mitochondrial dysfunction and enhance mitochondrial performance offer neuroprotection in PD. To delve into the role of mitochondrial function, we employed the synthetic PGC-1α activator ZLN005 to improve PD outcomes. In cellular PD model, we performed western blotting and immunofluorescence assays to assess disease-specific markers, including tyrosine hydroxylase and proteins related to mitochondrial biogenesis and regulation. Mitochondrial function was further evaluated using MitoTracker and ROS detection. We further investigated ZLN005 in a sub-acute MPTP mouse model. Motor performance was assessed, and subsequently, molecular analyses were conducted. Our findings revealed that ZLN005 significantly reduced MPP⁺/MPTP-induced neurotoxicity, improved motor deficits, and maintained the expression of PGC-1α, tyrosine hydroxylase, and other key mitochondrial markers involved in DNA replication and mitophagy. Notably, proteins that enhance PGC-1α transcription, including SIRT1, were also upregulated. In addition, the expression of mitochondrial fusion proteins increased, a pattern supported by elevated levels of other transcriptional regulators. Imaging and flow cytometry further confirmed that PGC-1α activation improved mitochondrial integrity and reduced oxidative stress. These results provide preliminary insights into the potential therapeutic role of PGC-1α activator in PD. ZLN005 has a neuroprotective effect in PD, which is elaborated by PGC-1α activator regulating the mitochondrial quality control system.

Methanol (MeOH) is a volatile and flammable liquid commonly used in the construction, automotive, and pharmaceutical industries. It has systemic and ocular toxicity, and most patients with methanol poisoning have severe metabolic acidosis. Occupational inhalation can cause toxic optic neuropathy and bilateral optic atrophy. In this study, we investigated whether the 5'-AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-alpha/sirtuin-3 (AMPK/PGC-1α/SIRT3) pathway is involved in the methanol-induced mitochondrial dysfunction. A series of behavioral, histological, and pathological assessments was performed. Methanol exposure slowed down the weight growth rate of rats and prolonged escape latencies. In addition, methanol exposure decreased the number of upright times and horizontal movements, damaged cortical neurons, and caused oxidative stress injury. These alterations coincided with neurobehavioral impairments, indicating that methanol exposure may cause oxidative damage and mitochondrial dysfunction by down-regulating the expression levels of the AMPK/PGC-1α/SIRT3 pathway proteins. Treatment with ZLN005, a PGC-1α activator, partially alleviated methanol-induced neurobehavioral deficits and mitochondrial dysfunction, likely via the modulation of the AMPK/PGC-1α/SIRT3 pathway, which may be a novel target for therapeutics aimed to alleviate the effects of environmental neurotoxicants.