Previously, in monkeys undergoing 20 min whole
brain ischemia we demonstrated that the activated
calpain-induced lysosomal disruption with the resultant leakage of
cathepsins B and L, causes neuronal death in the cornu Ammonis (CA) 1 sector on day 5. Selective
cathepsin inhibitors significantly protected ischemic CA1 neurons from delayed
necrosis. Recently,
pyridoxal phosphate (PLP) and
pyridoxal (hydrochloride) (PL) were demonstrated to inhibit
cathepsins B and L in vitro, because the active
aldehyde at position 4 of the
pyridine ring has an affinity for the active site -SH of
cysteine residues of
cathepsins. Here, we studied whether PLP and PL can, in vivo, protect monkey CA1 neurons from ischemic insult. In monkeys undergoing 20 min whole
brain ischemia, 15 mg/kg
body weight/day of drugs were intravenously injected for 10 days before and after the ischemic insult. Histological analysis of the surviving CA1 neurons was done using the hippocampus resected on day 5 after
ischemia. For PLP or PL, approximately 17% (P = 0.0639) or 54% (P < 0.0001) of the total population (100%) of control CA1 neurons were, respectively, saved from the
ischemia-induced neuronal death, showing a remarkable contrast to the surviving neurons (approximately 3.9%) in non-treated monkeys. These data suggested that PL (perhaps PLP intracellularly) is useful as a novel
neuroprotectant in primates.