Date of Award

11-5-2009

Degree Type

Thesis

Degree Name

PhD in Health Sciences

First Advisor

Anwar-ul-Hasan Gilani

Second Advisor

Saad Shafqat

Third Advisor

Kaneez Fatima-Shad

Department

Biological and Biomedical Sciences

Abstract

Curcuminoids (a mixture of curcumin, bisdemethoxycurcumin and demethoxycurcumin) share vital pharmacological properties possessed by turmeric, having therapeutic potential in the treatment of Alzheimer’s disease ( AD). Curcuminoids mixture and individual compounds were compared for their memory enhancing effect using different models of memory deficit. In the ex- vivo acetylcholinesterase assay, curcuminoids mixture and its individual constituents except curcumin showed dose-dependent (3-10 mg/kg) inhibition in frontal cortex and hippocampus. When studied for their effect on memory at a fixed dose (10 mg/kg), all compounds showed significant (p < 0.001) and comparable effect in scopolamine-induced amnesia in rats. In amyloid infused rat model of AD curcuminoids mixture showed memory enhancing effect in AD rats at 30 mg/kg, whereas, individual compounds were effective at 3-30 mg/kg. Curcuminoids mixture and bisdemethoxycurcumin increased PSD-95 level in hippocampus at 3-30 mg/kg after shorter duration treatment but were more effective at 3 mg/kg. Whereas, demethoxycurcumin and curcumin effectively increased PSD-95 only after long duration treatment at high dose (30 mg/kg). Curcuminoids mixture and individual compounds effectively increased synaptophysin level in hippocampus after longer duration treatment, where demethoxycurcumin was the most effective at 30 mg/kg dose. When studied for their effect on camkIV in hippocampus after longer duration treatment, only demethoxycurcumin at 30 mg/kg increased camkIV level.

To further explore their mechanism and provide cellular basis of memory enhancement, curcuminoids mixture and individual compounds were studied on Aβ peptide-induced LTP impairment in rat hippocampal slices. Curcuminoids mixture application, prior to high frequency stimulation, showed rescuing effect AD-induced LTP impairment only at lower dose of 0.1 KM (population spike (PS) potentiation) while, ineffective at higher doses (1 and 30 pM). Bisdemethoxycurcumin showed LTP induction in AB peptide treated slices only at a single dose of 0.1 pM, while, demethoxycurcumin showed effect at 1 pM. Curcumin effectively induced LTP at 30 and 1 FM, being the most effective amongst all three individual constituents.

This study was further extended to study effect of curcuminoids on mRNA levels of inflammatory and apoptotic markers. Curcuminoids mixture decreased IL-16 level in hippocampus at higher dose (30 mg/kg) studied after shorter duration treatment. Demethoxycurcumin was the only compound which effectively decreased IL-le in hippocampal area after shorter duration at 10 and 30 mg/kg and after longer duration at 30 mg/kg. When studied for their effect on caspase-3, curcuminoids mixture, bisdemethoxycurcumin and demethoxycurcumin showed different degree of effectiveness after longer duration treatment, whereas curcumin was devoid of effect. Treatment with curcuminoids mixture for short duration decreased GFAP levels in hippocampus whereas curcumin did not show effect. All of the compounds showed significant (p < 0.01) downregulation of fas receptor in hippocampal area after longer duration at each dose.

In summary, comparison of curcuminoids mixture and individual constituents indicated that, curcumin was found least effective in its acetylcholinesterase inhibitory effect while bisdemethoxycurcumin was the most effective. All compounds were equally effective in scopolamine-induced amnesia in rats. In Aβ infused AD model, curcumin was found more effective in memory enhancing. In case of the effect on inflammatory genes, demethoxycurcumin was found more effective than curcumin but comparable to the parent curcuminoids mixture, suggesting that this effect of curcuminoids mixture is due to the presence of demethoxycurcumin. All of these compounds showed downregulation of fas receptor in hippocampal area. Taken together, these data suggest that each constituent of the curcuminoids mixture contributes towards the pharmacological role of curcuminoids in AD and this study helps to understand pharmacological basis for the medicinal use of turmeric in AD.

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Last Page

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