NOS Inhibitors for Treatment of Motor Deficit Disorder (26093)

Northwestern scientists have prepared compositions that are powerful and highly selective for inhibiting neuronal NOS activity in the fetal brain and protecting fetal rabbit kits from HI-induced symptoms of cerebral palsy. The compositions appear to be nontoxic and show no detrimental cardiovascular effects.

ADVANTAGE: Novel neuronal nitric oxide synthase inhibitors that significantly reduce the incidence of cerebral palsy in fetal rabbits.

SUMMARY: Cerebral palsy is common in prematurely-born infants. The cost to society was estimated in 2002 at $8.2 billion for 750,000 persons affected in the US alone. There is no preventive treatment and little progress has been made in reducing the prevalence of cerebral palsy in recent years. Prenatal or fetal hypoxia-ischemia (HI) to the developing brain has been strongly implicated in the subsequent development of cerebral palsy in premature and full-term infants. A central role of nitric oxide (NO) has been implicated in cerebral injury caused by HI. An increase in the enzymatic activity of nitric oxide synthase (NOS) combined with a concomitant increase in the production of NO is pivotal in the pathophysiology of perinatal asphyxia. NO reacts with the generated superoxide (O2¯•) to produce peroxynitrite (ONOO¯), which contributes to protein or lipid nitrosylation and subsequent membrane lipid peroxidation, protein damage, and DNA damage. This invention provides new selective and bioavailable neuronal nitric oxide synthase inhibitors with low nanomolar potency and high isozyme selectivity to ameliorate these processes.

A clinically relevant model of acute placental insufficiency and global fetal HI that results in motor deficits resembling cerebral palsy in humans was employed. Isoform selective small molecules that decrease NO generated in HI brain were developed to control NO overproduction by nNOS while leaving the macrophage function of iNOS and the vasoprotective function of eNOS undisturbed, essential to safe administration for the treatment of fetal brain hypoxia-ischemia.

E22 New Zealand White rabbits subjected to 40 minutes of uterine ischemia result ten days later in postnatal motor deficits resembling cerebral palsy. A novel water soluble nNOS inhibitor (JI-8) was compared to 7-nitroindazole (7NI), which has been extensively used before. Maternal administration of JI-8, 30 minutes prior and immediately after uterine ischemia, resulted in a significant decrease in NOS activity (39%) and level of nitrogen oxides (48%) in fetal brain homogenates acutely after hypoxia-ischemia, without affecting maternal blood pressure and heart rate. Based on neurobehavior and tone, JI-8 treatment resulted in 18 normal kits, 5 moderately, 3 severely affected and 0 stillbirths, compared to 20 normal, 3 moderate, 5 severe and 10 stillbirths in the 7NI group. Both inhibitors of nNOS decreased motor deficits compared to saline treatment following fetal hypoxia-ischemia. However, JI-8 was superior to 7NI in its protection (p<0.05 Fisher’s Exact) and was particularly superior in terms of preventing stillbirths.

STATUS: Efforts continue to improve the activity and selectivity of these promising new compounds to reduce the onset of fetal cerebral palsy. Patents have been filed and Northwestern University seeks to develop the discovery.

Type of Offer: Licensing



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