Re: Thoughts on Creatine- Neuroprotection, obesity and Aspirin

[Guest guest]

Aspirin also affords good neuroprotection and, it seems, at nearly the

same doses used for thrombosis protection, though some evidence

suggests that it is effective at high doses as the following shows:

Brain Res. 2004 Feb 20;998(2):237-42.

High-dose aspirin is neuroprotective in a rat focal ischemia model.

Berger C, Xia F, Schabitz WR, Schwab S, Grau A.

Department of Neurology, University of Heidelberg, Im Neuenheimer Feld

400, Heidelberg, 69120, Germany.

Acetylsalicylic acid (ASA) is neuroprotective through various

pharmacological action sites. We used a temporary middle cerebral

artery occlusion (tMCAO) model in 56 Wistar rats to assess whether

repeated ASA injections at 30 min, 6 h, 1, 2, 3, and 4 days after

stroke onset are neuroprotective. Animals were sacrificed 5 days after

MCAO; infarct size was analyzed with 2,3,5-triphenyltetrazolium

chloride staining. As compared to saline (164+/-13 mm(3), n=14), only

repeated injections of 40 mg/kg ASA (79+/-18 mm(3), n=14, P=0.0029),

but not of 20 mg/kg ASA (129+/-19 mm(3), n=15), reduced infarct volume

significantly. No significant change was noted with 40 mg/kg ASA

injected only once at 30 min after MCAO (117+/-16 mm(3), n=13).

PMID: 14751595 [PubMed - indexed for MEDLINE]

But some authors think lower therapeutic doses are sufficient:

Neuropharmacology. 2000 Apr 27;39(7):1309-18.

Mechanisms of the neuroprotective effect of aspirin after oxygen

and glucose deprivation in rat forebrain slices.

Moro MA, De Alba J, Cardenas A, De Cristobal J, Leza JC, Lizasoain

I, -Guerra MJ, Bosca L, Lorenzo P.

Departamento de Farmacologia, Facultad de Medicina, Universidad

Complutense de Madrid (UCM), 28040, Madrid, Spain.

nlfucm@...

Acetylsalicylic acid (ASA, Aspirin) is an anti-inflammatory drug

with a wide spectrum of pharmacological activities and multiple sites

of action. Apart from its preventive actions against stroke due to its

antithrombotic properties, recent data in the literature suggest that

high concentrations of ASA also exert direct neuroprotective effects.

We have used an in vitro model of brain ischaemia using rat forebrain

slices deprived of oxygen and glucose to test ASA neuroprotective

properties. We have found that ASA inhibits neuronal damage at

concentrations lower than those previously reported (0.1-0.5 mM), and

that these effects correlate with the inhibition of excitatory amino

acid release, of NF-kappaB translocation to the nucleus and iNOS

expression caused by ASA. All of these three mechanisms may mediate

the neuroprotective effects of this drug. Our results also show that

the effects of ASA are independent of COX inhibition. Taken together,

our present findings show that ASA is neuroprotective in an in vitro

model of brain ischaemia at doses close to those recommended for its

antithrombotic effects.

PMID: 10760373 [PubMed - indexed for MEDLINE]

Of course the antiinflammatory, COX inhibiting , prostaglandin

inhibiting properties of aspirin are unequivocally well documented as

well as antiinflammatory effects independant of COX and protaglandin

inhibition.

Something else I found. Aspirin and other salcylates in general seem

to have the same effects as Metformin.

Science. 2001 Aug 31;293(5535):1673-7. Related Articles, Links

Reversal of obesity- and diet-induced insulin resistance with

salicylates or targeted disruption of Ikkbeta.

Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M,

Shoelson SE.

Joslin Diabetes Center and Department of Medicine, Harvard Medical

School, Boston, MA 02215, USA.

We show that high doses of salicylates reverse hyperglycemia,

hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing

insulin signaling. Activation or overexpression of the IkappaB kinase

beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas

IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather

than the cyclooxygenases, appears to be the relevant molecular target.

Heterozygous deletion (Ikkbeta+/-) protected against the development

of insulin resistance during high-fat feeding and in obese Lep(ob/ob)

mice. These findings implicate an inflammatory process in the

pathogenesis of insulin resistance in obesity and type 2 diabetes

mellitus and identify the IKKbeta pathway as a target for insulin

sensitization.

PMID: 11533494 [PubMed - indexed for MEDLINE]

Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S49-52. Related

Articles, Links

Click here to read

Inflammation and the IKK beta/I kappa B/NF-kappa B axis in

obesity- and diet-induced insulin resistance.

Shoelson SE, Lee J, Yuan M.

Joslin Diabetes Center & Department of Medicine, Harvard Medical

School, Boston, MA 02215, USA. .Shoelson@...

Antidiabetic effects associated with salicylates have been known

for years, although the underlying mechanisms were not understood. We

have been reinvestigating these effects in the light of recent

discoveries in the areas of signal transduction and insulin

resistance. Our findings showed that signaling pathways leading to I

kappa B kinase beta (IKK beta) and NF-kappa B are activated in

insulin-responsive tissues of obese and high-fat-fed animals. Since

activation correlates with the development of insulin resistance, we

asked whether signaling through this might be involved in the

pathogenesis of insulin resistance. Heterozygous gene deletion (Ikk

beta+/-) or salicylates, working as IKK beta inhibitors, improved

insulin sensitivity in insulin-resistant rodent models. Furthermore,

high doses of salicylates (aspirin or salicylate) improved insulin

sensitivity in patients with type II diabetes. Our studies implicate

an inflammatory process in the pathogenesis of insulin resistance in

obesity and type II diabetes mellitus and identify the IKK

beta/NF-kappa B pathway as a molecular mediator of insulin resistance

and pharmacological target for insulin sensitization.

Publication Types:

* Review

PMID: 14704745 [PubMed - indexed for MEDLINE]