From: http://cellceutix.com/autism/

AUTISM COMPOUND

KM-391 is a novel compound being developed for the treatment of autism. We acquired this compound late last year and have been working as rapidly as possible to learn more about its potential for development. Based on the initial research, we are very encouraged.

Autism is an area where there is a desperate need for new therapies. There are no drugs currently approved to treat the core conditions of autism. Autism affects as many as 1 in 100 births and takes a terrible toll on the families it affects. This is reflected in the many e-mails and calls we have received about our new compound.

Summary of the first animal studies with KM-391

Neonatal serotonin depletion and reduced plasticity of the brain are salient features observed in Autism. To experimentally induce these changes, 5,7-dihydroxytyptamine (5,7-DHT) was injected into the forebrain bundle on the day of birth of Wistar rat pups. Litter mates were injected with saline with progeny matched mice serving as controls.

5,7-DHT treated control rats significantly reduced their exploration in response to spatial rearrangement and object novelty, suggesting increased anxiety in response to change. A decrease in brain plasticity was observed, as well as a significant decrease in serotonergic (5-HT) innervation in the cortex and hippocampus; however, not in the subcortical forebrain. These changes and abnormalities are similar to our understanding of brain disorders presenting with cortical morphogenetic abnormalities and altered serotonin neurotransmission, as in Autism.

For the study, 100 µl of 5,7-DHT were injected 4 hours after birth. The animals were observed hourly for a few days until survival was established. Pair matching was done taking into consideration litter mating. Each group consisted of 10 male and 10 female rats with pair matching. KM-391 was given orally at 2.5 or 5 mg/kg; for comparison, fluoxetine was given at 5 mg/kg; and the 4th group served as 5,7-DHT-treated controls. The compounds were administered orally up to 90 days. The animals were scored for behavioral patterns, plasticity and serotonin levels. Behavioral scoring was done by standard behavioral test scoring, plasticity was calculated by surgical scoring, and serotonin levels were obtained by immunohistochemistry.

Conclusions

Treatment with KM-391 for 90 days resulted in:

Correction of abnormal behavior (p

Increased plasticity of brain ~ 85% by Day 100

Increase in brain serotonin levels to normal levels of paired twins (p

KM-391 second study at a prestigious research institute in India

Neonatal serotonin depletion and reduced plasticity of the brain are salient features observed in Autism. It has been shown that injection of 5,7-dihydroxytyptamine (5,7-DHT) into the forebrain bundle of Wistar rat pups on the day of birth will induce these changes. It has also been shown that oxytocin / vasopressin has a beneficial impact on repetitive behavior symptoms of autism, such as, touching, self-injury (Hollander 2003 Neuropharm 28:193), social behavior (Andari 2010 PNAS 107:4389), and emotion recognition (Guastella 2010 Biol Psychiatry 67:692). In this experiment, 5,7-DHT was injected into test animals, that induces certain conditions of autistic behavior, and an oxytocin antagonist was given to exacerbate these behavioral changes often observed in patients.

For the study, 5,7-DHT were injected 4 hours after birth. The animals were observed hourly for a few days until survival was established. Pair matching was done taking into consideration litter mating. Each group consisted of 5 male and 5 female rats with pair matching. To exacerbate behavioral changes, atosiban, an oxytocin antagonist, was administered to the pups by slow intravenous push. Then, KM-391 was given orally at 10 mg/kg. Two groups were given placebo in place of atosiban. Behavior was monitored for up to 8 hours after dosing. Standard behavioral test scoring was performed for: repetitive behavior, self-induced injury, sensitivity to touch, positioning correction, group dynamics, and curiosity. This procedure was repeated with the same animals on days 5 and 10.

The administration of an oxytocin antagonist alone consistently and significantly enhanced the autism-related behaviors. When KM-391 was given along with the oxytocin antagonist, there was a significant reduction in all 6 autism-related behaviors: repetitive behavior, self-induced injury, sensitivity to touch, positioning correction, group dynamics, and curiosity, within 1 to 2 hours. These support the testing of KM-391 as a possible therapeutic agent in the treatment of autistic behavior in patients.

KM-391 Third Study – Serotonin Levels Measured in Three Different Regions of the Brain

Neonatal serotonin depletion in the brain is an established observation observed in Autism. It has been shown that injection of 5,7-dihydroxytyptamine (5,7-DHT) into the forebrain bundle of Wistar rat pups on the day of birth will induce this depletion. In this experiment, serotonin levels were measured in three different regions of the brain in rats: cerebral cortex, hippocampus, or caudate nucleus, following either 5,7-DHT injection alone (induced autism), 5,7-DHT injection followed by 10 mg/kg KM-391 BID, or placebo treated controls.

For the study, two groups of rats were injected with 5,7-DHT 4 hours after birth. The animals were observed hourly for a few days until survival was established. Pair matching was done taking into consideration litter mating. Each group consisted of 5 male and 5 female rats with pair matching. A third group consisted of pups without 5,7-DHT injection. In one group KM-391 was given orally at 10 mg/kg BID for 40 days after 5,7-DHT injection. Two other groups were given placebo in place of KM-391. 48 days later, rats were sacrificed and brains were removed. Brains were sectioned, homogenized, and assayed for serotonin by ELISA.

Conclusions

The administration of KM 391 significantly (p<0.01) increased serotonin levels in all 3 regions of the brain:
cerebral cortex, hippocampus, and caudate nucleus, from very low levels as observed with 5,7-DHT-
induced autism to normal levels as observed in placebo treated control without the 5,7-DHT. These results
further support the testing of KM 391 as a possible therapeutic agent in the treatment of autism in patients.