Metabolism of a New Dipeptide Neuroprotector in Rats.

Metabolism of a new neuroprotector GZK-111 (N-phenylacetylglycyl-L-proline ethyl ester) in rat blood plasma was studied by HPLC-mass spectrometry. Four biotransformation products were identified. It is concluded that the main ways of GZK-111 biotransformation are hydrolysis of the ester bond by esterases followed by degradation of the resulting metabolite, as well as reactions leading to the formation of phenylacetic acid and cycloprolylglycine that exhibits neuropsychotropic activity.

Preclinical Pharmacokinetics of GZK-111, a Dipeptide with Neuroprotective Activity.

We studied the pharmacokinetics of GZK-111 (N-phenylacetyl-glycyl-L-proline ethyl ether), a compound with neuroprotective activity, and its metabolite CPG (cyclo-L-prolylglycine) in rat blood plasma after single intravenous and intragastric administration in a dose of 20 mg/kg. It was found that the parent drug undergoes intensive biotransformation; its metabolite CPG persists in the circulation more than twice as long as GZK-111 and its plasma concentrations were higher by 50-70 times than the concentrations of the parent compound.

Neuropeptide Cycloprolylglycine Exhibits Neuroprotective Activity after Systemic Administration to Rats with Modeled Incomplete Global Ischemia and in In Vitro Modeled Glutamate Neurotoxicity.

We studied cerebroprotective properties of neuropeptide cycloprolylglycine (1 mg/kg) administered intraperitoneally to rats with modeled incomplete global ischemia rats and neuroprotective properties for HT-22 cells under conditions of glutamate toxicity. It was shown that the neuropeptide administered during the postischemic period restored the neurological status of rats by preventing sensorimotor impairments in the limb-placing test and suppression of locomotor activity in the open field test. In in vitro experiments, cycloprolylglycine in concentrations of 10(-5)-10(-8) M exhibited pronounced dose-dependent neuroprotective activity. The results attest to high cerebro- and neuroprotective potential of endogenous peptide cycloprolylglycine.

Dipeptidylpeptidase 4 (DPP4, CD26) activity in the blood serum of term and preterm neonates with cerebral ischemia.

BACKGROUND: To investigate the mechanisms of inflammation in neonates after cerebral ischemia (CI), we evaluated the DPP4 activity in their blood sera and compared these values with clinical indicators. METHODS: The activity of DPP4 was determined in blood serum by a fluorescent method. We studied the correlation between the blood serum DPP4 activity and clinical, neurological and biochemical parameters in neonates with CI. RESULTS: No correlation between the DPP4 activity in umbilical blood and the venous blood of mothers was discovered. Increased blood serum DPP4 activity in full-term and pre-term newborns with CI is demonstrated. The interrelation between serum DPP4 activity and the functional disturbances of CNS (such as depression or excitement) was found in mature but not in premature newborns. Enzyme activity was still elevated at 2-3weeks after birth. CONCLUSION: It is possible that in neonates this enzymatic system operates independently from mothers. It is assumed that increased DPP4 activity in newborns with CI is apparently connected with immune system activation in response to hypoxic stress. The obtained data support the participation of DPP4 in adaptive reactions of newborns and its regulating influence during hypoxemic damage of the CNS due to inflammation and neurodegeneration.

Antihypoxic activity of cycloprolylglycine analogs.

We studied antihypoxic activity of analogs of endogenous cyclic dipeptide cycloprolylglycine in a mouse model of normobaric hypoxia with hypercapnia and found that antixypoxic effect depends on the structure of the substance. It was shown that different pharmacophores are responsible for the antihypoxic, nootropic, and anxiolytic effects of cycloprolylglycine.

Changes in activity of proline-specific peptidases in rat model for dementia of Alzheimer's type.

We studied the role of proline-specific peptidases in the pathogenesis of Alzheimer's disease. Testing of conditioned passive avoidance 24 h after learning showed that chronic administration of scopolamine to rats 4-fold reduced the latency of entry into the dark chamber in comparison with controls (intact animals). Activity of prolyl endopeptidase was significantly higher than in the controls in both the cortex and hippocampus. Changes in dipeptidyl peptidase IV activity were observed only in the cortex. Injection of AF-64A toxin into Meynert nucleus basalis reduced the latency of entry into the dark compartment by 75% in comparison with that in sham-operated and intact controls. Prolyl endopeptidase activity was reduced in the frontal cortex and hippocampus, but not in hypothalamus. Changes in dipeptidyl peptidase IV activity were detected only in the frontal cortex.

Effect of peripheral administration of peptide ligands of δ-opioid receptors on anxiety level and locomotor activity of rats.

We studied the effect of intragastric administration of a peptide δ-opioid receptor agonist DADLE and peptide δ-opioid receptor antagonist ICI 174.864 on anxiety and locomotor activity of rats. Peripheral administration of ICI 174.864 produced an anxiolytic effect, but did not modulate locomotor activity of rats. Agonist DADLE in doses of 50 and 100 µg/kg increased anxiety, but decreased locomotor activity of rats. Our results indicate that ICI 174.864 and DADLE produce opposite effects on anxiety in rats. These data support our hypothesis on the interaction between the central and peripheral compartments of the endogenous opioid system.