ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons, resulting in reduced dopamine levels in the brain. The exact cause of dopaminergic neuron loss remains unknown but factors such as increased oxidative stress (OS), neuroinflammation and mitochondrial dysfunction have been implicated in the progression of the disease. The behavioural and molecular repertoire of PD can be modelled in zebrafish larvae using a neurotoxin, 6-hydroxydopamine (6-OHDA). Currently, there is no cure for PD, however, medicinal plants such as Mesembryanthemum tortuosum may provide neuroprotective or neurorestorative benefits resulting from their psychoactive nature, which has been widely reported. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and neurorestorative effects of M. tortuosum extracts on 6-OHDA-induced deficits in zebrafish larvae. MATERIAL AND METHODS: The mesembrine alkaloid profiles of a methanol and acid-base extract of M. tortuosum and Zembrin® were obtained using ultra-performance liquid chromatography coupled to mass spectrometry. In the neuroprotection assay, zebrafish larvae at 2 days post-fertilisation (dpf) were treated concurrently with 6-OHDA (250.0 μM) and M. tortuosum extracts or Zembrin® (standardised commercial M. tortuosum), and incubated for 72 h. At the end of the incubation period, locomotion was monitored using high-throughput EthoVision XT tracking software, and the reactive oxygen species (ROS) and total glutathione content (tGSH) in the larvae were also assessed. In the neurorestoration assay, the 2 dpf larvae were initially pre-treated with 6-OHDA (250.0 μM) for 24 h, and the extracts or Zembrin® were added after 24 h and incubation proceeded for a further 48 h. Locomotion, ROS and tGSH were determined at the end of the 48 h incubation. Both assays utilised L-dopa and selegiline as the positive controls. RESULTS: The acid-base extract contained higher levels of Δ-mesembrenone and mesembrine compared to mesembranol and mesembrenone. Δ-Mesembrenone was identified as the major compound in the methanol extract, while Zembrin® contained mesembrenol, mesembranol, mesembrenone and mesembrine as major compounds. Zembrin® displayed the best neuroprotective activity by significantly attenuating locomotor deficits and increasing tGSH content at all the three tested concentrations. The methanol extract displayed the best neurorestorative activity significantly restoring tGSH content, locomotor activity and ROS at varying concentrations. CONCLUSIONS: The M. tortuosum extracts and Zembrin® containing various levels of mesembrine alkaloids improved both locomotion and oxidative stress associated with PD in a zebrafish larvae model. Furthermore, the effects of L-dopa and selegiline as core treatments in the management of PD were further confirmed in this PD zebrafish larvae model.