Effects of ML-9 on experimental delayed cerebral vasospasm

Area of Science:

• Neuroscience
• Pharmacology
• Vascular Biology

Background:

• Cerebral vasospasm is a critical complication following subarachnoid hemorrhage.
• Current treatments for cerebral vasospasm have limitations.
• Myosin light chain kinase (MLCK) plays a key role in vascular smooth muscle contraction.

Purpose of the Study:

• To evaluate the efficacy of 1-(5-chloronaphthalenesulfonyl)-1H-hexa-1,4-diazepine (ML-9) in reversing experimental delayed cerebral vasospasm.
• To determine the dose-dependent effects of ML-9 on basilar artery dilation.
• To assess the safety and tolerability of intracisternal ML-9 administration.

Main Methods:

• Experimental delayed cerebral vasospasm was induced in a canine model.
• The spastic basilar artery was accessed via a transclival approach.
• ML-9 was applied topically, injected into the cisterna magna, or infused into the vertebral artery.

Main Results:

• Topical ML-9 demonstrated dose-dependent dilation of the spastic basilar artery (median effective dose: 51.4 +/- 6.9 microM).
• Intracisternal injection of 50 microM ML-9 reversed angiographic vasospasm in 3 of 7 dogs.
• Vertebral artery infusion of 150 microM ML-9 resulted in minimal dilation.
• Intracisternal ML-9 at 50 microM did not cause significant electroencephalographic, hemodynamic, or histological abnormalities.

Conclusions:

• ML-9 is a potent vasodilator effective in reversing experimental cerebral vasospasm.
• ML-9 exhibits a favorable safety profile for intracisternal administration.
• ML-9 represents a promising therapeutic agent for managing cerebral vasospasm.