Function of dynorphin A (1-13) in ischemic brain injury

2024-07-09

Introduction 

Dynorphin A (1-13) [Dyn-A (1-13)] is a short-chain polypeptide containing 13 amino acids and having extensive biological activity in vivo. It is an important neurotransmitter in the central nervous system of the body. Dyn-A (1-13) can effectively delay the occurrence of cerebral edema and reduce cerebral ischemic injury, thus temporarily protecting the ischemic brain. Therefore, maintaining a certain concentration of Dyn-A (1-13) in the brain is important for protecting the ischemic brain and improving the subsequent damage caused by ischemia.

Pharmacologic action

The positive effects of Dyn-A (1-13) on cerebral ischemia and ischemic brain edema are mainly to counteract cerebral edema and to reduce the weight of the brain after ischemia to the level before ischemia. Excessive secretion of arginine vasopressin (AVP) leads to elevated intracranial pressure, causing edema, and Dyn-A (1-13) inhibits the secretion of arginine vasopressin by activating κ-type opioid receptors. In addition, the expression of Dyn-A (1-13) in the cerebral blood vessels can induce a sustained vasoconstriction effect, but it exerts a relaxing effect on the soft membrane arteries and small arteries, and this effect has a certain protective effect on brain tissue.

Function

A number of studies have shown that Dyn-A (1-13) reduces cerebral ischemic injury and produces significant neuroprotective effects. When the content of Dyn-A (1-13) in the ischemic brain area of experimental cerebral ischemia was significantly decreased, cerebral edema was aggravated, and cerebral edema was significantly relieved by injection of dynorphin A into the lateral ventricle. In experimental focal cerebral ischemia study, Dyn-A (1-13) can reach the normal hippocampus, cortex and cerebellum through the blood-brain barrier, and the blood-brain barrier is more abundant, which can be protected by the central mechanism. In addition, the lack of Dyn-A (1-13) will make the infarct volume larger and the condition worse.

Pharmacokinetics and metabolism

The major plasma metabolites of Dyn A(l-13) are Dyn A(1-12), A(2-12), A(4-12) and A4-8. Other metabolites are Dyn A(2-13), A(3-13), A(3-12), A(5-12), A(6-12), A(7-12), A(l-10), A(2-10), A(2-8) and A(3-8). The half-life of Dyn A(l-13) in plasma and blood is less than 1 minute at 37 °C. Intravenous administration of Dyn A(l-13) is very rapidly metabolized, with a major metabolite having a plasma half-life of 0.5 to 4 points. Side effects of tachycardia and flushing are usually observed. The incidence of side effects is dose dependent and is not affected by long-term opioid use.

References:

1. Chen CJ, Cheng FC, Liao SL, et al. Effects of naloxone lacate, pyruvate metabolism and antioxidant enzyme activity in rat cerebral ischemia/reperfusion [J]. J Neurosci Lett, 2000, 287(2), 113-116.

2. Turner TD, Browning JL, Widmayer MA, et al. Penetration of dynorphin1-13across the blood-brain barrier [J]. Neuropeptides, 1998, 32(2), 141-149.

3. Pedro L, Gambús MD, Thomas W. Schnider MD, et al. Pharmacokinetics of intravenous dynorphin A (1-13) in opioid-naive and opioid-treated human volunteers [J]. Clinical Pharmacology & Therapeutics, 1998, 64(1), 27-38.

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