Нейропептиды — это альтернатива современной фармакологии

2 130 комментариев / Научное и познавательное / От / 22.12.2019
Neirony

Нейропептиды           

В последнее время активно ведётся поиск высокоэффективных нейропротекторов среди нейропептидов. Новым направлением в исследовании нейропептидов стало определение их роли в регуляции апоптоза, а также влияния на экспрессию генов раннего реагирования.

Действие нейропептидов на организм

Нейропептиды свободно проникают через гематоэнцефалический барьер и оказывают многостороннее действие на ЦНС, что сопровождается высокой эффективностью и выраженной направленностью действия при условии их очень малой концентрации в организме.

Тесная взаимосвязь всех отдаленных последствий ишемии, а также общность их триггерных механизмов позволяют, наряду с локальным воздействием на них использовать модулирующие влияния через системы регуляторов, осуществляющих контроль над экспрессией вторичных клеточных мессенджеров, цитокинов и других сигнальных молекул, а также над запуском генетических программ апоптоза, антиапоптозной защиты, усиления нейротрофического обеспечения. Такие регуляторные (модуляторные) влияния устраняют общую дезинтеграцию во взаимодействии сложных и часто разнонаправленных молекулярно-биохимических механизмов, восстанавливая их нормальный баланс. Особо важную роль при этом играют эндогенные регуляторы функций ЦНС — нейропептиды [17]. Их молекулы, представляющие собой короткие аминокислотные цепи, «нарезаются» из более крупных белковых молекул-предшественников ферментами протеолиза («процессинг») лишь «в нужном месте и в нужное время» в зависимости от потребностей организма. Нейропептиды существуют всего несколько секунд, но длительность их действия может измеряться часами. Эндогенное образование нейропептида в ответ на какое-либо изменение внутренней среды приводит к высвобождению ряда других пептидов, для которых первый является индуктором. Если их совместное действие однонаправлено, эффект будет суммированным и продолжительным. Выход пептида может регулироваться несколькими регуляторными пептидами предыдущего каскада. Таким образом, эффекторная последовательность совокупности пептидов образует так называемый пептидный регуляторный континуум, особенность которого заключается в том, что каждый из регуляторных пептидов способен индуцировать или ингибировать выход ряда других пептидов. В результате, первичные эффекты того или иного пептида могут развиваться во времени в виде цепных и каскадных процессов.

Особенностью структуры нейропептидов является наличие нескольких лигандных групп связывания, предназначенных для разных клеточных рецепторов. Это одно из «молекулярных объяснений» присущей им полифункциональности. Физиологическая активность нейропептидов во много раз превышает аналогичное действие непептидных соединений. В зависимости от места их высвобождения, нейропептиды могут осуществлять медиаторную функцию (передачу сигнала от одной клетки к другой); модулировать реактивность определенных групп нейронов; стимулировать или тормозить выброс гормонов; регулировать тканевой метаболизм или выполнять функцию эффекторных физиологически активных агентов (вазомоторная, Na+-уретическая и другие виды регуляции). Известно, что нейропептиды способны регулировать активность про — и противовоспалительных цитокинов через модуляцию активности их рецепторов. При этом восстановление нормального баланса цитокинов происходит более эффективно, чем при воздействии на отдельные цитокиновые системы. Как правило, «цитокиновые» эффекты нейропептидов сопровождаются их влиянием на генерацию оксида азота и другие оксидантные процессы [19]. Многие нейропептиды проявляют выраженные нейротрофические ростовые свойства, а также способность регулировать экспрессию ранних генов. С учетом того, что нейропептиды легко проникают через гематоэнцефалический барьер (в отличие от полипептидных цепей факторов роста), трудно переоценить их потенциальную терапевтическую значимость.

Первый постулат: нейропептиды — универсальные регуляторы.

Второй постулат: пептиды построены как комбинации аминокислот — основных “кирпичиков» биологического мира.

Третий постулат: нейропептиды синтезируются в мозге (впрочем, в других органах тоже).

Четвертый постулат: биохимия синтеза пептидов едина для любых систем организма.

Пятый постулат: принцип “ЧТО? — ГДЕ? — КОГДА? ” как основной закон упорядоченной регуляторной миссии нейропептидов.

ПЕРВАЯ — ЧТО? Какой пептид (химическая и фармакологическая специфика)?

ВТОРОЕ — ГДЕ? В каком органе или в каких клетках экспрессируется его стимулированный синтез? Где предстоит пептиду работать как регулятору или исполнителю физиологического процесса?

ТРЕТЬЕ — КОГДА? В какой момент ритмично следующей или патологически нарушенной динамики физиологических процессов изменяется его активность?

Шестой постулат: рецептор — специализированная мембранная структура, где информационный сигнал превращается в физиологический акт.

Седьмой постулат: болезнь как нарушение соразмерности в биогенезе и рецепции нейропептидов. (5)

К нейропептидам относят любые пептиды, локализованные в нервной ткани и участвующие в регуляции функций ЦНС. В настоящее время известно около 100 нейропептидов, которые синтезируются различными популяциями нейронов мозга млекопитающих. Их молекулы, представляющие собой короткие аминокислотные цепи, «нарезаются» из более крупных белковых молекул-предшественников ферментами протеолиза (процессинг нейропептидов) лишь «в нужном месте и в нужное время» в зависимости от потребностей организма. Нейропептиды существуют всего несколько секунд, но длительность их действия может измеряться часами.

Обычно нейропептиды взаимодействуют с рецепторами посредством связывания с G-белком. Тогда как медиаторы воздействую на возбудимость других нейронов либо деполяризуя, либо гиперполяризуя их, нейропептиды обладают более широким спектром действия: они могут влиять на генную экспрессию, местный кровоток, образование синапсов и морфологию клеток нейроглии. Кроме того, в отличие от нейромедиаторов, они обладают продолжительным действием.

Нейропептиды имеют несколько групп связывания, предназначенных для разных клеточных рецепторов — это объясняет их полифункциональность. Физиологическая активность нейропептидов во много раз превышает действие непептидных соединений.

В течение последних десяти лет в ходе многочисленных клинических исследований были изучены эффекты многих нейропептидов на процессы нейродегенерации.

Для многих нейропептидов предложены «биологически активные конформации», обладая которыми пептид предпочтительно вступает во взаимодействие с рецептором.

Нейропептиды играют особую роль, так как являются эндогенными регуляторами функций ЦНС и имеющие ряд преимуществ перед другими группами нейропротективных препаратов:

высокая физиологическая активность (во много раз выше, чем у непептидных соединений);

наличие нескольких групп связывания для разных клеточных рецепторов и способность к регуляции экспрессии других сигнальных молекул, что обеспечивает многофункциональность нейропептидов;

короткое время жизни, обеспечивающее минимум побочных эффектов;

способность проникать через гематоэнцефалический барьер;

наличие трофических, ростовых, противовоспалительных, медиаторных и эффекторных свойств.

Так как многие нейропептиды проявляют выраженные нейротрофические ростовые свойства и легко проникают через гематоэнцефалический барьер (в отличие от полипептидных цепей факторов роста), трудно переоценить их потенциальную терапевтическую значимость.

Основной проблемой при применении нейропептидов для лечения является проблема доставки их в ЦНС: нейропептиды очень быстро разрушаются под действием особых пептидаз, время их действия очень ограничено, а потери по пути в ЦНС остаются большими. ведется работа по созданию нейропептидов, обладающих повышенной проникающей способностью через гематоэнцефалический барьер с использованием других путей введения, например, через назоталамический путь (через нос).

Нейропептиды: противовоспалительное действие.

Известно, что нейропептиды способны регулировать активность про — и противовоспалительных цитокинов через модуляцию активности их рецепторов. При этом восстановление нормального баланса цитокинов происходит более эффективно, чем при воздействии на отдельные цитокиновые системы. Как правило, цитокиновые эффекты нейропептидов сопровождаются их влиянием на образование NO (оксида азота) и другие.

Нейропептиды против апоптоза.

Новым направлением в исследовании нейропептидов стало определение их роли в регуляции апоптоза. Существует определенная параллель между информацией об участии нейропептидов и нейротрофических факторов роста в развитии неврологических расстройств и причастностью этих химических регуляторов к апоптозу нейронов. Нейротрофические ростовые факторы можно разделить на те, которые играют роль индукторов апоптоза в нервной ткани и те, которые противодействуют его развитию.

Так, например, короткие фрагменты ADNF ADNF-14 ADNF-9 предотвращают смерть нейронов при БА. Нейропептид NAD, состоящий из 8 аминокислот и сходный по строению с ADNF, предотвращал когнитивные нарушения у моделей с БА.

Такие свойства этих нейропептидов свидетельствуют о том, что их можно рассматривать как возможные терапевтические агенты для лечения психоневрологических расстройств, связанных с нейродегенерацией.

Нейропептиды — биологически активные соединения, синтезируемые в нервных клетках. Нейропептиды:

участвуют в регуляции обмена веществ и поддержании гомеостаза,

воздействуют на иммунные процессы,

играют важную роль в механизмах памяти, обучения, сна и др.

могут действовать как медиаторы и гормоны. (6)

Влияние нейропептидов на выработку интерферонов.

Многие неврологические заболевания сопровождаются развитием иммунодефицитного состояния, о чем свидетельствует нарушение продукции цитокинов, в частности в системе интерферонов. К таким заболеваниям относится острое нарушение мозгового кровообращения (ОНМК), болезнь Альцгеймера, травматические повреждения головного мозга, а также различные нейроинфекционные заболевания. Результаты проведенных клинических исследований показали, что использование нейропептидов (на моделе церебролизина) приводит к нормализации нарушенных показателей иммунитета при остром инсульте, болезне Альцгеймера, у часто и длительно болеющих детей с минимальной мозговой дисфункцией, а также при нейроинфекционных заболеваниях. По скольку головной мозг является одним из регуляторов иммунной системы, то очевидно, что препарат, полученный из головного мозга (церебролизин), способен оказывать регулирующее действие на иммунную систему. Предложена гипотеза о том, что механизм нейроиммунокорригирующего действия церебролизина обусловлен не только специфической нейротрофической активностью, сходной с эффектом фактора роста нервов, но и индукцией интерферона, который в свою очередь обладает противовирусной, иммуномодулирующей и антипролиферативной активностью. Лечебный эффект церебролизина у больных с ОНМК, нейроинфекционными заболеваниями, деменцией альцгеймеровского типа (дефицитной по интерферону) и травматическим повреждением головного мозга может быть связан с индукцией интерферона, который в свою очередь корригирует дисбаланс нейроиммунной системы.

Нейропептиды (на модели церебролизина) оказывают как прямое (индукция интерферона), так и опосредованное (нейротрофичк; еский эффект) иммунокорригирующее действие при многих неврологических заболеваниях, сопровождающихся нарушениями иммунной системы. (10)

Нейропептиды-лекарства.

В последние годы все больше и больше внимания уделяется изучению и поиску новых способов нейропротективной терапии.

Нейропептиды являются щелочными полипептидами, имеющие молекулярную массу от 1000 до 10000Да. Их получают из тканей сетчатки и головного мозга с помощью кислой экстракции с последующей очисткой от балластных веществ. Данный метод получения исключает возможность переноса вирусов и протоонкогенов, что обеспечивает безопасность применения данных веществ в клинической практике.

Нейропептиды обладают способностью индуцировать процессы специфической дифференцировки в популяции клеток, являющимися исходным материалом для их получения.

Они влияют на клеточный и гуморальный иммунитет, состояние системы гомеастаза, ПОЛ и другие защитные реакции организма. Это действие выражено в разной степени и зависит от применяемой дозы.

Механизмы действия нейропетидов в настоящее время не до конца ясен. По всей видимости, их эффекты осуществляются через специфические рецепторы, расположенные на поверхности клетки. После экзогенного введения полипептидов происходит выброс эндогенных регуляторных пептидов, для которых введенный пептид является индуктором. Эффект пептидного каскада приводит к пролонгированию эффекта нейропептидов, который сохраняется даже после полного разрушения первоначального индуктора.

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