New Drug May Help Rescue The Aging Brain
(Mar. 31, 2008) â€” As people age, their brains pay the price â€” inflammation goes up, levels of certain neurotransmitters go down, and the result is a plethora of ailments ranging from memory impairment and depression to Alzheimerâ€™s and Parkinsonâ€™s. But in a long-term study with implications to treat these and other conditions, researchers have found that an experimental drug, taken chronically, has the ability to stem the effects of aging in the rat brain.
The drug, temporarily designated S18986, interacts with AMPA (short for Î±- Amino-3-hydroxy-5- methylisoxazole-4- propionic acid, or ampakine) receptors in the brain. These receptors transmit excitatory signals in the brain, and
researchers were interested in experimental AMPA-receptor drugs (such as S18986) for their neuroprotective abilities and for the way they temporarily boost memory. But rather than investigating the compoundâ€™s short-term effects, Alfred E. Mirsky Professor Bruce McEwen and his lab members made a far longer commitment: The scientists studied the drugâ€™s impacts on middle-aged to elderly rats and found that, when administered daily over four consecutive months, it appeared to improve memory and slow brain aging.
â€œNobody had ever looked at the long-term effects of these ampakines on the aging brain,â€ says McEwen, head of Rockefellerâ€™s Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. Short-term studies, he notes, had shown that the drug appears to improve aspects of memory, likely by temporarily ramping up AMPA receptors in the hippocampus â€” the brainâ€™s memory and learning center. But McEwen, research assistant Erik Bloss and postdocs Elizabeth Waters and Richard Hunter found that, over the course of four months, S18986 changed the entire profile of the older rodentsâ€™ brains.
When compared to control animals that had received only sugar water, the drugged rats were not only more active and better at memory tests, but their brains showed physical signs of slowed aging. Neurons in the forebrain that produce acetylcholine, a neurotransmitter known to play a role in learning and memory, had 37 percent less decline. Dopamine-producing neurons, which are responsible for sustaining activity and motivation levels, slowed their decline by 43 percent. Levels of inflammation in the brain were also significantly lower. â€œEvery marker we chose to look at seemed to indicate there was some preservation of function during aging with chronic treatment,â€ Hunter says. The drug appears to slow agingâ€™s effects throughout the entire brain.
Dopamine is a motivation- and movement-related neurotransmitter in the brain, and its presence is necessary for maintaining normal activity levels â€” itâ€™s the chemical that helps you get up off the couch and socialize or exercise. A severe loss of dopamine production causes Parkinsonâ€™s disease, â€œso this drug has the potential, perhaps, to block the progression of the disease,â€ Hunter says.
Not only that, but it could be helpful for much less severe conditions, too. As people age, itâ€™s often harder for them to feel motivated to socialize or even eat, leading to depression and making latent conditions worse. â€œSo maybe this drug isnâ€™t going to be the one that prevents Parkinsonâ€™s,â€ Waters says, â€œbut maybe itâ€™s going to improve the quality of life as you age, so that up until the very end of your life you can sustain that quality and sustain a higher activity level.â€
With such a variety of impacts on neurotransmitters, S18986 holds enormous potential. But so far, itâ€™s only potential. The researchers hope to dig deeper to find out precisely how the drug works. â€œThereâ€™s a lot to be done,â€ Hunter says, â€œand this shows that thereâ€™s broad potential for these compounds.â€
Reference: Experimental Neurology 210(1):109â€“117 (March, 2008)