Greek Sage Exhibits Neuroprotective Activity against Amyloid Beta-Induced Toxicity.

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting the elderly at a high incidence. AD is of unknown etiology and currently, no cure is available. Present medication is restricted to treating symptoms; thus, a need exists for the development of effective remedies. Medicinal plants constitute a large pool, from which active compounds of great pharmaceutical potential can be derived. Various Salvia spp. are considered as neuroprotective, and here, the ability of Salvia fruticosa (SF) to protect against toxic effects induced in an AD cell model was partly assessed. Two of AD's characteristic hallmarks are the presence of elevated oxidative stress levels and the cytotoxic aggregation of amyloid beta (Aß) peptides. Thus, we obtained SF extracts in three different solvents of increasing polarity, consecutively, to evaluate (a) their antioxidant capacity with the employment of the free radical scavenging assay (DPPH•), of the ferric reducing ability of plasma assay (FRAP), and of the cellular reactive oxygen species assay (DCFDA) and (b) their neuroprotective properties against Aß 25-35-induced cell death with the use of an MTT assay. All three SF extracts showed a considerable antioxidant capacity, with the methanol (SFM) extract being the strongest. The results of the total phenolic and flavonoid contents (TPC and TFC) of the extracts and of the FRAP and the DCFDA assays showed a similar pattern. In addition, and most importantly, the dichloromethane (SFD) and the petroleum ether (SFP) extracts had an effect on Aß toxicity, exhibiting a significant neuroprotective potential. To our knowledge, this is the first report of SF extracts demonstrating neuroprotective potential against Aß toxicity. In combination with their antioxidant capacity, SF extracts may be beneficial in combating AD and other neurodegenerative diseases.

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.