title: ÐÐ½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ðµ NMDA ÑÐµÑÐµÐ¿ÑÐ¾ÑÐ¾Ð² Ð±Ð¸Ð³ÑÐ°Ð½Ð¸Ð´Ð½ÑÐ¼Ð¸ ÑÐ¾ÐµÐ´Ð¸Ð½ÐµÐ½Ð¸ÑÐ¼Ð¸
title: Ð²ÑÐ¿ÑÑÐºÐ½Ð°Ñ ÐºÐ²Ð°Ð»Ð¸ÑÐ¸ÐºÐ°ÑÐ¸Ð¾Ð½Ð½Ð°Ñ ÑÐ°Ð±Ð¾ÑÐ° Ð±Ð°ÐºÐ°Ð»Ð°Ð²ÑÐ°
titleType: Subtitle
title: Inhibition of NMDA receptors by biguanide compounds
Creators: name: ÐÐ¾Ð²Ð¸ÐºÐ¾Ð²Ð°, ÐÐ½Ð°ÑÑÐ°ÑÐ¸Ñ
Publisher: name: Ð¡Ð°Ð½ÐºÑ-ÐÐµÑÐµÑÐ±ÑÑÐ³ÑÐºÐ¸Ð¹ Ð¿Ð¾Ð»Ð¸ÑÐµÑÐ½Ð¸ÑÐµÑÐºÐ¸Ð¹ ÑÐ½Ð¸Ð²ÐµÑÑÐ¸ÑÐµÑ ÐÐµÑÑÐ° ÐÐµÐ»Ð¸ÐºÐ¾Ð³Ð¾
Year: 2024
Subjects: Ð¿Ð°ÑÑ-ÐºÐ»Ð°Ð¼Ð¿
ÑÐµÑÐµÐ¿ÑÐ¾ÑÑ
Ð±Ð¸Ð³ÑÐ°Ð½Ð¸Ð´Ð½ÑÐµ ÑÐ¾ÐµÐ´Ð¸Ð½ÐµÐ½Ð¸Ñ
ÑÐ¸ÐºÐ»Ð¾Ð³ÑÐ°Ð½Ð¸Ð»
Ð¼Ð¾ÑÐ¾ÐºÑÐ¸Ð´Ð¸Ð½
ÑÐµÐ½ÑÐ¾ÑÐ¼Ð¸Ð½
Ð¼ÐµÑÑÐ¾ÑÐ¼Ð¸Ð½
Ð¿ÑÐ¾Ð³ÑÐ°Ð½Ð¸Ð»
Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ðµ
patch-clamp
receptors
biguanide compounds
cycloguanil
moroxydine
phenformin
metformin
proguanil
inhibition

description: ÐÐ¸Ð³ÑÐ°Ð½Ð¸Ð´Ñ â ÑÑÐ¾ ÑÐ¾ÐµÐ´Ð¸Ð½ÐµÐ½Ð¸Ñ, ÑÐ¾Ð´ÐµÑÐ¶Ð°ÑÐ¸Ðµ Ð´Ð²Ðµ Ð³ÑÐ°Ð½Ð¸Ð´Ð¸Ð½Ð¾Ð²ÑÐµ Ð³ÑÑÐ¿Ð¿Ñ, ÑÐ¾ÐµÐ´Ð¸Ð½ÑÐ½Ð½ÑÐµ Ð² ÐµÐ´Ð¸Ð½ÑÑ ÑÐ¾Ð¿ÑÑÐ¶ÑÐ½Ð½ÑÑ ÑÐ¸ÑÑÐµÐ¼Ñ. ÐÐ°Ð½Ð½Ð°Ñ ÑÐ°Ð±Ð¾ÑÐ° Ð¿Ð¾ÑÐ²ÑÑÐµÐ½Ð° Ð¸Ð·ÑÑÐµÐ½Ð¸Ñ Ð´ÐµÐ¹ÑÑÐ²Ð¸Ñ ÑÑÐ´Ð° ÑÐ¾ÐµÐ´Ð¸Ð½ÐµÐ½Ð¸Ð¹ ÑÑÐ¾Ð¹ Ð³ÑÑÐ¿Ð¿Ñ â Ð¿ÑÐ¾ÑÐ¸Ð²Ð¾Ð¼Ð°Ð»ÑÑÐ¸Ð¹Ð½ÑÑ Ð¿ÑÐµÐ¿Ð°ÑÐ°ÑÐ¾Ð² Ð¿ÑÐ¾Ð³ÑÐ°Ð½Ð¸Ð»Ð° Ð¸ ÑÐ¸ÐºÐ»Ð¾Ð³ÑÐ°Ð½Ð¸Ð»Ð°, Ð³Ð¸Ð¿Ð¾Ð³Ð»Ð¸ÐºÐµÐ¼Ð¸ÑÐµÑÐºÐ¸Ñ Ð¿ÑÐµÐ¿Ð°ÑÐ°ÑÐ¾Ð² Ð¼ÐµÑÑÐ¾ÑÐ¼Ð¸Ð½Ð° Ð¸ ÑÐµÐ½ÑÐ¾ÑÐ¼Ð¸Ð½Ð° Ð¸ Ð¿ÑÐ¾ÑÐ¸Ð²Ð¾Ð²Ð¸ÑÑÑÐ½Ð¾Ð³Ð¾ Ð¿ÑÐµÐ¿Ð°ÑÐ°ÑÐ° Ð¼Ð¾ÑÐ¾ÐºÑÐ¸Ð´Ð¸Ð½Ð° â Ð½Ð° Ð¸Ð¾Ð½Ð¾ÑÑÐ¾Ð¿Ð½ÑÐµ Ð³Ð»ÑÑÐ°Ð¼Ð°ÑÐ½ÑÐµ ÑÐµÑÐµÐ¿ÑÐ¾ÑÑ NMDA ÑÐ¸Ð¿Ð°. Ð­ÐºÑÐ¿ÐµÑÐ¸Ð¼ÐµÐ½ÑÑ Ð¿ÑÐ¾Ð²Ð¾Ð´Ð¸Ð»Ð¸ÑÑ Ð½Ð° Ð½Ð°ÑÐ¸Ð²Ð½ÑÑ ÑÐµÑÐµÐ¿ÑÐ¾ÑÐ°Ñ Ð¿Ð¸ÑÐ°Ð¼Ð¸Ð´Ð½ÑÑ Ð½ÐµÐ¹ÑÐ¾Ð½Ð¾Ð² Ð³Ð¸Ð¿Ð¿Ð¾ÐºÐ°Ð¼Ð¿Ð° ÐºÑÑÑ Ð»Ð¸Ð½Ð¸Ð¸ ÐÐ¸ÑÑÐ°Ñ. ÐÐ»Ñ Ð¸Ð·Ð¾Ð»ÑÑÐ¸Ð¸ Ð½ÐµÐ¹ÑÐ¾Ð½Ð¾Ð² Ð¸Ð· ÑÑÐµÐ·Ð¾Ð² Ð¸ÑÐ¿Ð¾Ð»ÑÐ·Ð¾Ð²Ð°Ð»ÑÑ Ð¼ÐµÑÐ¾Ð´ Ð²Ð¸Ð±ÑÐ¾Ð´Ð¸ÑÑÐ¾ÑÐ¸Ð°ÑÐ¸Ð¸, Ð° Ð´Ð»Ñ ÑÐµÐ³Ð¸ÑÑÑÐ°ÑÐ¸Ð¸ ÑÐ¾ÐºÐ¾Ð² Ð¼ÐµÑÐ¾Ð´ ÑÐ¸ÐºÑÐ°ÑÐ¸Ð¸ Ð¿Ð¾ÑÐµÐ½ÑÐ¸Ð°Ð»Ð° Ð² ÐºÐ¾Ð½ÑÐ¸Ð³ÑÑÐ°ÑÐ¸Ð¸ ÑÐµÐ»Ð°Ñ ÐºÐ»ÐµÑÐºÐ°. ÐÑÐ»Ð¾ Ð²Ð¿ÐµÑÐ²ÑÐµ Ð¿Ð¾ÐºÐ°Ð·Ð°Ð½Ð¾, ÑÑÐ¾ ÑÐ¸ÐºÐ»Ð¾Ð³ÑÐ°Ð½Ð¸Ð», Ð¿ÑÐ¾Ð³ÑÐ°Ð½Ð¸Ð» Ð¸ ÑÐµÐ½ÑÐ¾ÑÐ¼Ð¸Ð½ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÑÑÑ NMDA ÑÐµÑÐµÐ¿ÑÐ¾ÑÑ Ð² Ð¼Ð¸ÐºÑÐ¾Ð¼Ð¾Ð»ÑÑÐ½ÑÑ ÐºÐ¾Ð½ÑÐµÐ½ÑÑÐ°ÑÐ¸ÑÑ, ÐÐ50 ÑÐ¾ÑÑÐ°Ð²Ð¸Ð»Ð¸ 3,4 Â± 0,6, 9,0 Â± 2,2 Ð¸ 13 Â± 1 Ð¼ÐºÐ, ÑÐ¾Ð¾ÑÐ²ÐµÑÑÑÐ²ÐµÐ½Ð½Ð¾. ÐÐµÑÑÐ¾ÑÐ¼Ð¸Ð½ Ð¸ Ð¼Ð¾ÑÐ¾ÐºÑÐ¸Ð´Ð¸Ð½, Ð½Ð°Ð¿ÑÐ¾ÑÐ¸Ð², Ð¾ÐºÐ°Ð·Ð°Ð»Ð¸ÑÑ Ð¿ÑÐ°ÐºÑÐ¸ÑÐµÑÐºÐ¸ Ð½Ðµ Ð°ÐºÑÐ¸Ð²Ð½Ñ. ÐÐ½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ðµ Ð²ÑÐµÐ¼Ð¸ Ð°ÐºÑÐ¸Ð²Ð½ÑÐ¼Ð¸ ÑÐ¾ÐµÐ´Ð¸Ð½ÐµÐ½Ð¸ÑÐ¼Ð¸ Ð±ÑÐ»Ð¾ Ð½ÐµÐºÐ¾Ð½ÐºÑÑÐµÐ½ÑÐ½ÑÐ¼. Ð­ÑÑÐµÐºÑÐ¸Ð²Ð½Ð¾ÑÑÑ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ ÑÐ¸ÐºÐ»Ð¾Ð³ÑÐ°Ð½Ð¸Ð»Ð¾Ð¼ Ð¼Ð¾Ð½Ð¾ÑÐ¾Ð½Ð½Ð¾ ÑÐ¾ÑÐ»Ð° Ð¿ÑÐ¸ Ð³Ð¸Ð¿ÐµÑÐ¿Ð¾Ð»ÑÑÐ¸Ð·Ð°ÑÐ¸Ð¸ Ð¼ÐµÐ¼Ð±ÑÐ°Ð½Ñ, ÑÐ²Ð¸Ð´ÐµÑÐµÐ»ÑÑÑÐ²ÑÑ Ð¾ Ð±Ð»Ð¾ÐºÐ°Ð´Ðµ Ð¿Ð¾ÑÑ ÐºÐ°Ð½Ð°Ð»Ð° ÐºÐ°Ðº Ð¾ÑÐ½Ð¾Ð²Ð½Ð¾Ð¼ Ð¼ÐµÑÐ°Ð½Ð¸Ð·Ð¼Ðµ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ. ÐÐµÐ¹ÑÑÐ²Ð¸Ðµ Ð¿ÑÐ¾Ð³ÑÐ°Ð½Ð¸Ð»Ð° Ð¸ ÑÐµÐ½ÑÐ¾ÑÐ¼Ð¸Ð½Ð°, Ð½Ð°Ð¿ÑÐ¾ÑÐ¸Ð², Ð² Ð¾ÑÐ½Ð¾Ð²Ð½Ð¾Ð¼ Ð±ÑÐ»Ð¾ Ð¿Ð¾ÑÐµÐ½ÑÐ¸Ð°Ð»-Ð½ÐµÐ·Ð°Ð²Ð¸ÑÐ¸Ð¼ÑÐ¼, ÑÐ²Ð¸Ð´ÐµÑÐµÐ»ÑÑÑÐ²ÑÑ Ð² Ð¿Ð¾Ð»ÑÐ·Ñ Ð°Ð»Ð»Ð¾ÑÑÐµÑÐ¸ÑÐµÑÐºÐ¾Ð³Ð¾ Ð¸Ð½Ð³Ð¸Ð±Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ. ÐÐ¾Ð»ÑÑÐµÐ½Ð½ÑÐµ Ð´Ð°Ð½Ð½ÑÐµ Ð¼Ð¾Ð³ÑÑ ÑÐ¿Ð¾ÑÐ¾Ð±ÑÑÐ²Ð¾Ð²Ð°ÑÑ ÑÐµÐ¿Ð¾Ð·Ð¸ÑÐ¸Ð¾Ð½Ð¸ÑÐ¾Ð²Ð°Ð½Ð¸Ñ Ð´Ð°Ð½Ð½ÑÑ Ð¿ÑÐµÐ¿Ð°ÑÐ°ÑÐ¾Ð² Ð´Ð»Ñ Ð»ÐµÑÐµÐ½Ð¸Ñ Ð½ÐµÐ¹ÑÐ¾Ð´ÐµÐ³ÐµÐ½ÐµÑÐ°ÑÐ¸Ð²Ð½ÑÑ Ð·Ð°Ð±Ð¾Ð»ÐµÐ²Ð°Ð½Ð¸Ð¹, ÑÐ²ÑÐ·Ð°Ð½Ð½ÑÑ Ñ ÑÑÐµÐ·Ð¼ÐµÑÐ½Ð¾Ð¹ Ð°ÐºÑÐ¸Ð²Ð°ÑÐ¸ÐµÐ¹ Ð¸Ð¾Ð½Ð¾ÑÑÐ¾Ð¿Ð½ÑÑ Ð³Ð»ÑÑÐ°Ð¼Ð°ÑÐ½ÑÑ ÑÐµÑÐµÐ¿ÑÐ¾ÑÐ¾Ð², Ð° ÑÐ°ÐºÐ¶Ðµ Ð»ÑÑÑÐµ Ð¾Ð±ÑÑÑÐ½Ð¸ÑÑ Ð¸Ñ Ð¿Ð¾Ð±Ð¾ÑÐ½ÑÐµ ÑÑÑÐµÐºÑÑ.
description: Biguanide compounds consist of two guanidine groups connected in a single conjugated system. The given work is devoted to investigating the action of several compounds from this group â antimalarial medicines cycloguanil and proguanil, anti-hyperglycemic agents metformin and phenformin and antiviral medicine moroxydine â on NMDA type ionotropic glutamate receptors. Experiments were performed on Wistar rat isolated hippocampal pyramidal neurons from CA1 area. Cells were isolated from slices by vibrodissociation. Whole cell patch clamp method was used to record the transmembrane currents. Metformin and moroxydine were found to be practically inactive against NMDA receptors. Cycloguanil, proguanil and phenformin inhibited them with IC50 values of 3,4 Â± 0,6, 9,0 Â± 2,2 Ð¸ 13 Â± 1 ÂµM, respectively. The action of all active compounds was not competitive. The inhibition by cycloguanil monotonically increased with hyperpolarization of the membrane evidencing channel pore block as the major molecular mechanism of action. In contrast, the inhibition by proguanil and phenformin was mostly voltage-independent suggesting allosteric inhibition. These data may help to support the repurposing of investigated compounds for the treatment of neurodegenerative diseases linked to glutamate excitotoxicity, as well as better understanding their side effects.