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 TGFβ1, IL1β 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.