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Drug found to thwart mental decline, grow brain cells in rodents

July 8, 2010
Courtesy of Cell Press,
National Institutes of Health
and World Science staff

Sci­en­tists have dis­cov­ered a chem­i­cal that they say re­stores mem­o­ry-forming ca­pac­ity in ag­ing rats, like­ly by pro­mot­ing the sur­viv­al and growth of new cells in the brain’s mem­o­ry hub. 

The re­search has turned up clues to a mech­an­ism that could lead to a treat­ment for Alzheimer’s dis­ease, the in­ves­ti­ga­tors said.

The com­pound may work si­m­i­larly to two drugs al­ready stud­ied as a treat­ment for the mem­ory-rob­bing ill­ness—one of them with dis­ap­point­ing re­cent re­sults, they added. On the brighter side, they went on, their find­ings point the way to pos­sib­ly much stronger drugs that work by a si­m­i­lar mech­an­ism.

The com­pound P7C3 was found by test­ing more than 1000 small mo­le­cules in mice. Its chem­i­cal struc­ture is in­di­cat­ed by the stand­ard­ized di­a­gram at right. (Cred­it: An­drew Pieper, UT South­west­ern Med­i­cal Cen­ter)


“This strik­ing demon­stra­t­ion… points the way to po­ten­tial de­vel­op­ment of the first cures that will ad­dress the co­re ill­ness pro­cess in Alzheimer’s dis­ease,” said Thom­as In­sel, di­rec­tor of the U.S. Na­tional In­sti­tute of Men­tal Health, which partly funded the re­search.

The new­found sub­stance, called P7C3, “holds spe­cial promise” be­cause it’s safe­ly tol­er­ated in mice, can be tak­en orally and en­ters the brain eas­i­ly, said said re­searcher Ste­ven Mc­Knight, who co-led the in­ves­ti­ga­t­ion with An­drew Pieper, both of Uni­vers­ity of Tex­as South­west­ern Med­i­cal Cen­ter. The sci­en­tists re­port on their find­ings Ju­ly 9 in the re­search jour­nal Cell.

Phys­i­cal ac­tiv­ity and en­rich­ing ex­pe­ri­ences pro­mote the birth and matura­t­ion of new brain cells called neu­rons, re­search­ers say. This takes place in the den­tate gy­rus, a key ar­ea of the brain’s mem­o­ry hub, the hip­po­cam­pus. But most of these new­born neu­rons die dur­ing the month it takes to de­vel­op and get wired in­to brain cir­cuit­ry. To sur­vive, the cells must run a gaunt­let of chal­lenges. New­born hip­po­cam­pus neu­rons fare much worse in ag­ing-related dis­or­ders like Alzheimer’s, marked by run­away cell death.

“It takes a long time—two to four weeks—from the birth of a new neu­ron un­til it be­comes func­tion­al,” Mc­Knight said. “Most of them die along the way.”

In hopes of find­ing com­pounds that might pro­tect these vul­ner­a­ble cells, Pieper, Mc­Knight and col­leagues tested more than 1,000 small mo­le­cules in mice. They found that one, P7C3, cor­rected deficits in the brains of adult mice en­gi­neered to lack a gene needed for the new­born neu­rons’ sur­viv­al.

“We really did­n’t know if the screen would turn up a fa­vor­a­ble com­pound,” said Mc­Knight. “It was blind luck.”

Giv­ing the chem­i­cal to the mice re­duced pro­grammed death of new­born cells, the group said, nor­mal­iz­ing stunted growth of branch-like neu­ronal ex­ten­sions and thick­en­ing an ab­nor­mal ly thin lay­er of cells by 40 per­cent. Among clues to the mech­an­ism by which P7C3 works, the re­search­ers found that it pro­tects the in­tegr­ity of ma­chin­ery for main­tain­ing a cel­l’s en­er­gy lev­el.

To find out if it could al­so stem ag­ing-associated neu­ronal death and cog­ni­tive de­cline, the re­search­ers al­so gave the com­pound to aged rats. These treated ro­dents sig­nif­i­cant ly out­per­formed peers on a wa­ter maze task, a stand­ard test of hip­po­cam­pus-dependent learn­ing, the re­search­ers said. This was traced to a three­fold higher-than-normal lev­el of new­born neu­rons in the den­tate gy­rus of the treated an­i­mals.

The re­search­ers pin­pointed a de­riv­a­tive of P7C3, called A20, which they said is even more pro­tective than the par­ent com­pound. They al­so pro­duced ev­i­dence sug­gest­ing that two oth­er com­pounds stud­ied as pos­sible Alzheimer’s cures may work through the same mech­an­ism as P7C3.

These drugs, called Dime­bon and Serono, bear struc­tur­al si­m­i­lar­i­ties to P7C3 and en­cour­age new neu­rons to grow, the in­ves­ti­ga­tors said. Dime­bon came to sci­en­tists’ at­ten­tion based on an­ec­do­tal re­ports by Rus­sian doc­tors that it may help at­ten­u­ate age-related cog­ni­tive de­cline. Un­for­tu­nate­ly, un­pub­lished re­ports from a phase 3 clin­i­cal tri­al have since failed to show the drug’s ef­fec­tive­ness against Alzheimer’s. In light of the new find­ings, it may be worth anoth­er look, the sci­en­tists said.

The A20 de­riv­a­tive proved an es­ti­mat­ed 300 times more po­tent than Dime­bon, they added, sug­gest­ing even stronger brain-pro­tective agents could po­ten­tially be dis­cov­ered us­ing si­m­i­lar meth­ods. Fol­low­ing up on these leads, the they’re now search­ing for which mo­le­cules in the brain are af­fect­ed by P7C3, key to dis­cov­er­ing its un­der­ly­ing mech­an­ism of ac­tion.


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Scientists have discovered a chemical that they say restores memory-forming capac ity in aging rats, like ly by promoting the survival and growth of new cells in the brain’s memory hub. The research has turned up clues to a mechanism that could lead to a treatment for Alzheimer’s disease, the investigators said. The compound may work similar ly to two drugs already studied as an Alzheimer’s treatment—one of them with disappointing recent results, they added. On the brighter side, they went on, their findings point the way to possib ly much stronger drugs that work by a similar mechanism. The newfound substance, called P7C3, “holds special promise” because it’s safe ly tolerated in mice, can be taken oral ly and enters the brain easily, said said researcher Steven McKnight, who co-led the investigation with Andrew Pieper, both of Univers ity of Texas Southwestern Medical Center. The scientists report on their findings Ju ly 9 in the research journal Cell. “This striking demonstration… points the way to potential development of the first cures that will address the core illness process in Alzheimer’s disease,” said Thomas Insel, director of the U.S. National Institute of Mental Health, which part ly funded the research. Physical activ ity, social, or other enriching experiences promote the birth and maturation of new brain cells called neurons, researchers say. This takes place in the dentate gyrus, a key area of the brain’s memory hub, the hippocampus. But most of these newborn neurons die during the month it takes to develop and get wired into brain circuitry. To survive, the cells must run a gauntlet of challenges. Newborn hippocampus neurons fare much worse in aging-related disorders like Alzheimer’s, marked by runaway cell death. “It takes a long time – two to four weeks—from the birth of a new neuron un til it becomes functional,” McKnight said. “Most of them die along the way.” In hopes of finding compounds that might protect these vulnerable cells, Pieper, McKnight and colleagues tested more than 1,000 small molecules in mice. They found that one, P7C3, corrected deficits in the brains of adult mice engineered to lack a gene needed for the newborn neurons’ survival. “We real ly didn’t know if the screen would turn up a favorable compound,” said McKnight. “It was blind luck.” Giving the chemical to the mice reduced programmed death of newborn cells, the group said, normalizing stunted growth of branch-like neuronal extensions and thickening an abnormal ly thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers found that it protects the integr ity of machinery for maintaining a cell’s energy level. To find out if it could also stem aging-associated neuronal death and cognitive decline, the researchers also gave the compound to aged rats. These treated rodents significant ly outperformed peers on a water maze task, a standard test of hippocampus-dependent learning, the researchers said. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. The researchers pinpointed a derivative of P7C3, called A20, which they said is even more protective than the parent compound. They also produced evidence suggesting that two other compounds studied as possible Alzheimer’s cures may work through the same mechanism as P7C3. These drugs, called Dimebon and Serono, bear structural similar ities to P7C3 and encourage new neurons to grow, the investigators said. Dimebon came to scientists’ attention based on anecdotal reports by Russian doctors that it may help attenuate age-related cognitive decline. Un fortunately, un published reports from a phase 3 clinical trial have since failed to show the drug’s effectiveness against Alzheimer’s. In light of the new findings, it may be worth another look, the scientists said. The A20 derivative proved an estimated 300 times more potent than Dimebon, they added, suggesting even stronger brain-protective agents could potential ly be discovered using similar methods. Following up on these leads, the they’re now searching for which molecules in the brain are affected by P7C3, key to discovering its un derlying mechanism of action.