Regulation of Neprilysin Activity and Cognitive Functions in Rats After Prenatal Hypoxia.

The amyloid-degrading enzyme neprilysin (NEP) is one of the therapeutic targets in prevention and treatment of Alzheimer's disease (AD). As we have shown previously NEP expression in rat parietal cortex (Cx) and hippocampus (Hip) decreases with age and is also significantly reduced after prenatal hypoxia. Following the paradigms for enhancement of NEP expression and activity developed in cell culture, we analysed the efficacy of various compounds able to upregulate NEP using our model of prenatal hypoxia in rats. In addition to the previous data demonstrating that valproic acid can upregulate NEP expression both in neuroblastoma cells and in rat Cx and Hip we have further confirmed that caspase inhibitors can also restore NEP expression in rat Cx reduced after prenatal hypoxia. Here we also report that administration of a green tea catechin epigallocatechin-3-gallate (EGCG) to adult rats subjected to prenatal hypoxia increased NEP activity in blood plasma, Cx and Hip as well as improved memory performance in the 8-arm maze and novel object recognition tests. Moreover, EGCG administration led to an increased number of dendritic spines in the hippocampal CA1 area which correlated with memory enhancement. The data obtained allowed us to conclude that the decrease in the activity of the amyloid-degrading enzyme NEP, as well as a reduction in the number of labile interneuronal contacts in the hippocampus, contribute to early cognitive deficits caused by prenatal hypoxia and that there are therapeutic avenues to restore these deficits via NEP activation which could also be used for designing preventive strategies in AD.

The role of the cholinergic system of the sensorimotor cortex of the rat brain in controlling different types of movement.

The role of the cholinergic system of the sensorimotor cortex of the Wistar rat brain in controlling various types of movements was assessed by studying the effects of microinjections of carbachol and scopolamine into the representation area of the forelimb on the performance of two types of fore-limb food-procuring movements--with and without pressure on an obstacle--as well as on the animals' locomotion. These studies showed that administration of the cholinergic agonist carbachol (0.03-3 microg) leads to slowing of both types of procuring movements and acceleration of locomotor activity in an open field. Injections of the cholinergic antagonist scopolamine (0.3-3 microg) into the same area accelerated procuring movements, while the animals' locomotor activity remained unaltered. These data indicate that the cholinergic system of the sensorimotor cortex has different regulatory influences on movement activity (locomotion) and the performance of learned movements requiring forelimb muscle tone to be maintained for different periods of time (the usual rapid movements used for extracting food from a narrow horizontal tube versus slow movements with additional tactile and tonic components).

[The participation of the cholinergic system of the rat sensorimotor cortex in regulating different types of movements]. / Uchastie kholinergicheskoi sistemy sensomotornoi kory mozga krysy v reguliatsii raznykh tipov dvizhenii.

To study the role of the cholinergic system of the sensorimotor cortex in regulation of different manipulatory movements and locomotion of Wistar rats, the effects of injections of cholinergic drugs (a cholinergic agonist carbachol and an antagonist scopolamine) into the area of forepaw representation in the sensorimotor cortex on motor activity and performance of manipulatory movements (with prolonged and short pushing) were analyzed. The drugs were injected via special cannulae stereotaxically implanted into the cortex during surgery carried out under Nembutal anesthesia. Carbachol injections (0.03-3 micrograms in 1 microliter of physiologic solution) into the cortex resulted in a significant slowing down of both types of movements as well as an increase in locomotion in the open-field test. Injections of scopolamine (0.3-3 micrograms) into the same cortical area were accompanied by an increase in the number of fast manipulatory movements without significant changes in locomotor activity. The obtained evidence suggests that the cholinergic system of the sensorimotor cortex indifferent manners regulates the innate (locomotion) and acquired movements which require different periods of maintaining the muscle tone of the forepaw (short-time periods for the usual movements necessary for food taking from the narrow horizontal tube and prolonged periods for the learned slow movements with additional tactile and tonic components).

Neurochemical characteristics of the rat neostriatum and motor cortex after the development of a unilateral manipulatory reflex.

Indicators of the activity of acetylcholinesterase (ACE), 5'-nucleotidase (NT), adenylate cyclase (AC) in the sensorimotor cortex and the neostriatum (NS) of the right and left cerebral hemispheres of control rats and rats trained to perform a food-procuring movement by pressing against an obstacle with the forelimb. An identical level of the averaged bilateral values of the activity of NT and AC in both of the structures in question and an increased ACE activity in the NS were found in the control animals. After the development of a manipulatory skill, the activity of AC decreased in the cortex and the NS in the presence of unchanged ACE activity, while NT activity decreased in the cortex and increased in the NS. The bilateral values of the activity of the enzymes differed significantly in well and poorly trained rats. At the same time, the activity of the enzymes was similar in character in the dominant and subdominant hemispheres for each group of animals. Overall the neurochemical changes obtained can be regarded as specific correlates of the developed unilateral manipulatory reactions that are characteristic for the structures in question of both cerebral hemispheres.

[The neurochemical characteristics of the rat neostriatum and motor cortex after the acquisition of a unilateral manipulatory reflex]. / Neirokhimicheskie kharakteristiki neostriatuma i motornoi kory krysy posle vyrabotki odnostoronnego manipuliarnogo refleksa.

The activity of acetylcholinesterase (AChE), 5'-nucleotidase (NT) and adenylate cyclase (AC) were studied in sensomotor cortex and neostriatum (NS) from right and left hemispheres of control and experimental rats, trained to perform food reaching with pushing on operant by preferable forepaw. The levels of summarized bilateral activity of NT as well as of AC were found to be similar in both studied structures of control rats, while the activity of AChE was higher in NS than in cortex. In trained rats the activity of AC was decreased both in cortex and NS, the activity of NT was decreased in cortex and increased in NS, AChE being not changed when compared with control. The bilateral values of enzyme activities in well and badly learning rats were significantly different. Meanwhile, when the dominant and subdominant hemispheres were compared these values were found to be similar. In general, the results obtained could be evaluated as specific features of conditioned unilateral manipulatory reactions, characteristic for cortex and NS of brain hemispheres.

[The effect of a toxic dose of ammonium chloride on brain bioelectrical activity in rats]. / Vliianie toksicheskoi dozy khloristogo ammoniia na bioélektricheskuiu aktivnost' mozga krys.

A toxic dose of ammonium chloride (> 12 mmol/kg) caused death of animals within 10 min of i.p. injection, while pentobarbital--(40 mg/kg, i.p.) and kurare--(0.2 mg/kg, i.v.) injected rats died only in 11% of the tests. At 40 min after the injection of NH4Cl, the kurare-treated animals had minimum EEG amplitude in the cortex, maximum--in RF, and unchanged in amygdala. At the same time evoked potentials (EP) in RF induced by the periphery stimuli remained unchanged in form and increased in amplitude. Corticofugal impulses had no specific influence on the formation of EP in RF. The initial potentials were restored within 3 hrs. Thus, it could be concluded that ammonium differentiatively changed the state of the normal brain functional systems; it increased the afferentation and excitation of RF which could lead to violation of the vitally important functions especially breathing and cause the lethal outcome.

[Afferent and central mechanisms of the osmoregulating reflex from the liver following hypothalamic deafferentation]. / Afferentnyi i tsentral'nyi mekhanizmy osmoreguliruiushchego refleksa s pecheni pri deafferentatsii gipotalamusa.

In anesthetized cats, 52 units of the hypothalamic supraoptic nuclei out of 65 retained the ability to respond to the osmotic stimulation after dissection of the brain stem (cerveau isolé). Administration of 1.0 ml 5% NaCl solution into the v. porta decreased the firing rate in 9 units and increased it in 43 units. The latency and the maximum reaction time were 30-100 sec and 2-6 min, resp. The data obtained suggest a humoral link in the reflex from the liver osmoreceptors.