SkQR1 Reduces Neurologic Deficit Caused by Rat Brain Compression Ischemia.

The protective effect of antioxidant SkQR1 was examined on the model of left-sided compression ischemia in rat sensorimotor cortex. The special tests aimed to determine the neurologic deficit in the limbs and assess performance of the forelimbs showed that a 2.5-min ischemia produced no disturbance in the limb functions on postsurgery days 1, 3, and 7. Elevation of compression time resulted in neurologic deficit in animals, and its severity depended on this time. A single intravenous injection of SkQR1 (250 nmol/kg body weight) performed 30 min after ischemia significantly reduced the degree of neurologic deficit. In vitro model of ischemia in surviving rat hippocampal slices showed that a 15-min-long ischemia significantly inhibited the population excitatory postsynaptic potentials, which did not restore during reperfusion. Preincubation of the slices with SkQR1 did not significantly affect recovery of these potentials.

GK-2 Reduces Death of Cultured Granule Neurons in Cerebellum Induced by the Toxic Effects of Zinc Ions.

Peptide mimetic of nerve growth factor GK-2 in a dose of 1-2 mg/liter improves survival of cultured rat cerebellar granule neurons exposed to the cytotoxic effect of zinc ions, but has no protective effect against copper ion cytotoxicity. Experiments on cultured rat hippocampal slices demonstrated that GK-2 did not affect reactivity of pyramidal neurons and long-term potentiation in the hippocampal field CA1 and the probability of glutamate release from presynaptic terminals in the synapses of the CA3-CA1 fields. The results suggest that GK-2 does not affect the functional properties of synaptic transmission under normal conditions, but protects neurons from the toxic effects of zinc, which creates prerequisites for GK-12 use in the treatment of neurodegenerative diseases.

The involvement of sigma1 receptors in donepezil-induced rescue of hippocampal LTP impaired by beta-amyloid peptide.

Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptor (Sig1-R). Beta-amyloid peptide (Aß) is believed to contribute to the pathogenesis of AD. In our previous work (Kapai et al., 2012), we have shown that donepezil antagonizes the suppressive action of Aß(1-42) on long-term potentiation (LTP) in rat hippocampal slices. The purpose of the present study was to determine whether Sig1-R is involved into the mechanisms of donepezil action. For this purpose, we have tested whether agonist of Sig1-R PRE-084 mimics, and antagonist of Sig1-R haloperidol abolishes the effect of donepezil. Population spikes (PSs) were recorded from the pyramidal layer of the CA1 region of rat hippocampal slices. Drugs were applied by addition to the perfusate starting 15 min before and ending 5 min after the tetanus. In the control group, the amplitude of PS 30 min post-tetanus reached 153±10%. Aß (200 nM) markedly suppressed the LTP magnitude or even caused the suppression of baseline PS (82±8%, P<0.001). This suppression of LTP could be markedly prevented when 1 µM donepezil was co-administered with Aß (136±11%, P<0.05). Further, we co-administered three substances: Aß, donepezil and 0.5 µM haloperidol and have found that haloperidol antagonized the stimulating effect of donepezil on LTP (92±6%, P<0.05). Agonist of Sig1-R PRE-084 (0.1-10 µM) enhanced control LTP and abolished the inhibitory effect of Aß on LTP in a concentration-dependent manner. The amplitude of PS 30 min post-tetanus reached 183±7% (P<0.01) for 10 µM PRE-084. The results suggest that activation of Sig1-R is involved into the mechanisms of donepezil-induced rescue of hippocampal LTP impaired by Aß.