ABSTRACT
The mechanisms of the neuroprotective action of the hexapeptides HLDF-6 encoded by the amino acid sequence 41-46 of Human Leukemia Differentiation Factor and its homoserine derivative HLDF-6H were studied in an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD). C57Bl/6 mice received two intraperitoneal injections of 18 mg/kg MPTP-HCl, with an interval of 2 hours. MPTP-induced motor dysfunction was assessed using horizontal grid test. Our data show that chronic intranasal administration of peptides (3 weeks, 300 µg/kg/day) restored normal levels of dopamine and improved its turnover rates in the striatum. Furthermore, peptide administration increased serum estradiol levels and led to a significant improvement in motor functions in MPTP-treated mice. Additionally, peptide treatment increased the levels of mRNA encoding neurotrophin BDNF, but normalized the levels of mRNA encoding the inflammatory mediators TGFß1, IL1ß and IFNγ in the brain. Collectively, our behavioral and biochemical studies demonstrate that HLDF-6 peptides have a therapeutic potential for treating PD. We propose that HLDF-6 peptides may exert their neuroprotective mechanism, at least in part, by normalizing estradiol levels and modulating the expression of key factors involved in neurotrophic support and neuroinflammation.
