Re: Re: Autism, Other Disorders Linked To Post-Natal Factors: Study

[Guest guest]

Rapamycin has an effect on mTOR, but I wouldn't venture a guess as to

whether it would have the right effect. And there are so many other

metabolic problems, it's not clear (and doubtful I'd think) that

simple correction of one pathway would restore everything - although

there have been a few kids who have apparently recovered completely

upon chelation alone I think. Here's a abstract form an article on

this:

" “TOR’’RENTS OF EXCITEMENT OVER RAPAMYCIN’S ANTIEPILEPTOGENIC POTENTIAL "

Epilepsy Currents, Vol. 8, No. 6 (November/December) 2008 pp. 163–165

" Response of a Neuronal Model of Tuberous Sclerosis to Mammalian

Target of Rapamycin (mTOR) Inhibitors:

Effects on mTORC1 and Akt Signaling Lead to Improved Survival and

Function. Meikle L, Pollizzi K, Egnor A,

Kramvis I, Lane H, Sahin M, Kwiatkowski DJ. J Neurosci 2008;28(21):

5422–5432. Tuberous sclerosis (TSC) is a hamartoma

syndrome attributable to mutations in either TSC1 or TSC2 in which

brain involvement causes epilepsy, mental retardation, and

autism. We have reported recently (Meikle et al., 2007) a mouse

neuronal model of TSC in which Tsc1 is ablated in most neurons

during cortical development. We have tested rapamycin and RAD001 [40-

O-(2-hydroxyethyl)-rapamycin], both mammalian target of

rapamycin mTORC1 inhibitors, as potential therapeutic agents in this

model. Median survival is improved from 33 d to more than 100 d;

behavior, phenotype, and weight gain are all also markedly improved.

There is brain penetration of both drugs, with accumulation over time

with repetitive treatment, and effective reduction of levels of

phospho-S6, a downstream target of mTORC1. In addition, there is

restoration of phospho-Akt and phospho-glycogen synthase kinase 3

levels in the treated mice, consistent with restoration of

Akt function. Neurofilament abnormalities, myelination, and cell

enlargement are all improved by the treatment. However, dysplastic

neuronal features persist, and there are only modest changes in

dendritic spine density and length. Strikingly, mice treated with

rapamycin or RAD001 for 23 d only (postnatal days 7–30) displayed a

persistent improvement in phenotype, with median survival of

78 d. In summary, rapamycin/RAD001 are highly effective therapies for

this neuronal model of TSC, with benefit apparently attributable to

effects on mTORC1 and Akt signaling and, consequently, cell size and

myelination. Although caution is appropriate, the results suggest the

possibility that rapamycin/RAD001 may have benefit in the treatment

of TSC brain disease, including infantile spasms.

Rapamycin Prevents Epilepsy in a Mouse Model of Tuberous Sclerosis

Complex. Zeng LH, Xu L, Gutmann DH,

Wong M. Ann Neurol 2008;63(4):444–453. OBJECTIVE: Tuberous sclerosis

complex (TSC) represents one of the most common

genetic causes of epilepsy. TSC gene inactivation leads to

hyperactivation of the mammalian target of rapamycin signaling pathway,

raising the intriguing possibility that mammalian target of rapamycin

inhibitors might be effective in preventing or treating epilepsy in

patients with TSC. Mice with conditional inactivation of the Tsc1

gene primarily in glia (Tsc1GFAPCKO mice) develop glial

proliferation, progressive epilepsy, and premature death. Here, we

tested whether rapamycin could prevent or reverse epilepsy, as well

as other cellular and molecular brain abnormalities in Tsc1GFAPCKO

mice. METHODS: Tsc1GFAPCKO mice and littermate control animals were

treated with rapamycin or vehicle starting at postnatal day 14 (early

treatment) or 6 weeks of age (late treatment), corresponding to times

before and after onset of neurological abnormalities in Tsc1GFAPCKO

mice. Mice were monitored for seizures by serial

videoelectroencephalogram and for long-term survival. Brains were

examined histologically for astrogliosis and neuronal organization.

Expression of phospho-S6 and other molecular markers correlating with

epileptogenesis was measured byWestern blotting. RESULTS: Early

treatment with rapamycin prevented the development of epilepsy and

premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late

treatment with rapamycin suppressed seizures and prolonged survival

in Tsc1GFAPCKO mice that had already developed epilepsy.

Correspondingly, rapamycin inhibited the abnormal activation of the

mammalian target of rapamycin pathway, astrogliosis, and neuronal

disorganization, and increased brain size in Tsc1GFAPCKO mice.

INTERPRETATION: Rapamycin has strong efficacy for preventing seizures

and prolonging survival in Tsc1GFAPCKO mice. "

> Is there anything that restores this function? My d went downhill

> rapidly after a short[less than 5 wk] course of valproic acid.

> Thanks,

>