PDE-5 Inhibitor Sildenafil Improves Cognition, or Viagra's Good for the Big Head Too

Inspired by Rush Limbaugh's apparent erectile dysfunction, I decided that today's Evil Journal Club should address the "other" potential uses of PDE-5 inhibitors, the most (in)famous of which is Viagra.

Phosphodiesterase type 5 (PDE-5) is an enzyme that breaks down cyclic GMP. We've known for a while that cGMP is important for signal transduction and ultimately for learning and memory processes, and that nitric oxide (NO) can stimulate production of cGMP. Interestingly, changes in this NO-cGMP signaling pathway have been implicated in aging, providing a potential link to deteriorating cognition with increased age. PDE-5 inhibitors such as sildenafil citrate (Viagra) may therefore act to improve cognition by preventing the enzyme PDE-5 from breaking down cGMP.

The paper in discussion today sought to test this possibility by first demonstrating that memory performance could be impaired by administration of a drug called L-NAME, which blocks NO production by disrupting the activity of the enzyme nitric oxide synthase (NOS). By blocking NOS, L-NAME decreases the amount of NO, which ultimately decreases levels of cGMP and produces cognitive impairment. The primary hypothesis of the paper can then be tested-- does inhibition of PDE-5 prevent learning and memory impairments by ensuring that the remaining cGMP does not get broken down?

The researchers measured memory by use of the 14 unit T maze


Basically, a rat learns to make its way from start to finish, and the number of wrong turns (errors) are recorded. A rat can be tested under the influence of different drugs to determine if the drugs enhance the rate at which the maze is learned (fewer errors over time), memory (fewer errors in later trials but similar numbers of errors while learning), etc.

So the treatments in this study consisted of:

1. Control--- to establish baseline
2. L-NAME-- to demonstrate that NOS inhibition can produce behavioral impairments
3. L-NAME + Sildenafil-- to demonstrate that Sildenafil can prevent behavioral impairments

Four doses of Sildenafil were tested-- 1, 1.5, 3, and 4.5 mg/kg. Multiple doses are used to establish the most effective amount, because pharmacologically we tend to see the proverbial U-shaped curve, where there is an increasing benefit up to a certain dose, then as you continue to go higher performance steadily drops off.

Results are presented as follows: Errors are on the Y axis, and trials are reported on the X axis (trials are grouped together in blocks of three for convenience).

The results:


As you can see, rats that received L-NAME (upside-down triangles) consistently made significantly more errors than the control rats (dark circles) as trials progressed, and it appears that the 1.5 mg/kg dose of Sildenafil (diamonds) could attenuate the effect of L-NAME; their performance is almost equal to that of control animals. If you look at the inset of the figure, you can see the average number of errors across all the blocks of trials. Two asterisks (**) indicate that the L-NAME group performed worse than control, and one asterisk (*) indicates that the 1.5 mg/kg dose of Sildenafil was effective at reversing this impairment.

So in conclusion, Sildenafil can prevent learning impairments produced by inhibiting NOS. While these benefits seem tightly correlated to a narrow dose range of Sildenafil, they join a growing body of literature that suggests PDE-5 inhibitors may provide benefits for the aging individual, beyond those for which they are marketed (to put it politely). These results suggest that the NO-cGMP pathway may be a viable target for drugs that seek to prevent or reverse age-related impairments in learning and memory.

Source: Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition
Psychopharmacology (Berl). 2006 Jan;183(4):439-45. Epub 2005 Nov 18.

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