Navigation Links
Novel 'prodrug' alleviates symptoms in Huntington's and Alzheimer's mice

A study in a special early online publication of Cell, a Cell Press publication, reveals a promising new slow-release compound that protects mice against the neurodegenerative effects of both Huntington's and Alzheimer's disease. The 'prodrug' known only as JM6 works through a pathway involved in the breakdown of the amino acid tryptophan.

Surprisingly, JM6 delivers those benefits even though it doesn't cross the blood-brain barrier and therefore cannot act directly on the brain.

"Most would have assumed that the drug would have to enter the brain to have an effect," said Paul Muchowski of the University of California, San Francisco. He says the new study may therefore pave the way to new strategies for the treatment of brain diseases more broadly.

The kynurenine pathway is a major route of tryptophan breakdown. Scientists had suspected the pathway to play a role in neurodegeneration since the late 1970s, Muchowski said. Metabolites of the pathway can lead to excessive stimulation of neurons, causing damage and even death of the cells.

Muchowski's team started with a compound earlier designed to target an enzyme called kynurenine 3-monooxygenase or KMO.When KMO is inhibited, it shunts the kynurenine pathway in a direction that increases production of a neuroprotective compound known as kynurenic acid (KYNA). KYNA levels are known to decline in Huntington's and Alzheimer's brains.

But the researchers found that the starting compound (Ro 61-8048) was unstable and degraded quickly. Fortunately for Muchowski, his recently retired father Joseph Muchowski is a synthetic chemist with experience in drug development. He enlisted him in generating a slow-release prodrug version of the KMO inhibitor, which they call JM6.

They first treated mice with Huntington's disease with JM6. Chronic delivery of JM6 inhibited KMO in the animals' blood, increasing kynurenic acid levels and reducing extracellular levels of the chemical messenger glutamate in the brain. Those mice, which normally would have died by the time they were 15 weeks old, lived about 40 percent longer than they otherwise would have, Muchowski said. Their motor coordination improved and they were protected against the loss of the synapses that serve as critical junctions in the neural circuitry.

In a transgenic mouse model of Alzheimer's disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and the loss of synapses. "JM6 helped the animals remember," Muchowski said.

Alzheimer's mice also become uninhibited and will run right out of the safety of the dark and into open spaces, a risky habit in the real world where predators lurk. "JM6 completely rescued that deficit."

Muchowski says the preservation of synapses they observed is especially key. That's because it's known that memory loss in Alzheimer's correlates more closely with the loss of synapses than with the loss of neurons.

Muchowski said they do plan to test the drug's use in humans through clinical trials. Since JM6 is a new compound, they will have to start with trials designed to test the safety and toxicity of the drug. He expects the first trials could be underway in about two year's time in patients with Huntington's disease.

"One way or another, we will move forward," he said.


Contact: Elisabeth Lyons
Cell Press

Related biology news :

1. Scientists identify novel inhibitor of human microRNA
2. Conaway Lab identifies novel mechanism for regulation of gene expression
3. LIAI launches new division to look at novel approaches to heart disease and inflammation
4. Childrens National researchers develop novel anti-tumor vaccine
5. Cold Spring Harbor Laboratory scientists trace a novel way cells are disrupted in cancer
6. Novel publishing approach puts textbook in more hands
7. GEN reports on novel tools for deciphering biological networks
8. UT Southwestern researcher awarded Gates Foundation grant for novel vaccine development
9. 3-substituted indolones as novel therapeutic compounds for neurodegenerative conditions
10. Corn researchers discover novel gene shut-off mechanisms
11. A novel target for therapeutics against Staph infection
Post Your Comments:
(Date:11/20/2015)... , November 20, 2015 ... company focused on the growing mobile commerce market and ... Gino Pereira , was recently interviewed on ... will air on this weekend on Bloomberg Europe ... America . --> NXTD ) ("NXT-ID" or ...
(Date:11/18/2015)... --> --> ... report titled  Gesture Recognition Market - Global Industry Analysis, ... to the report, the global gesture recognition market was valued at ... US$29.1 bn by 2021, at a CAGR of 20.3% ... dominated the global gesture recognition market in ...
(Date:11/17/2015)... 17, 2015 Pressure BioSciences, Inc. (OTCQB: PBIO) ... and sale of broadly enabling, pressure cycling technology ("PCT")-based ... today announced it has received gross proceeds of $745,000 ... Placement (the "Offering"), increasing the total amount raised to ... additional closings are expected in the near future. ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... MUMBAI , November 26, 2015 ... --> Accutest Research ... accredited Contract Research Organization (CRO), has ... Chase Cancer Center - Temple Health ... ,     (Photo: ) ...
(Date:11/25/2015)... BRUSSELS , November 25, 2015 ... in cat and human plaque and pave the way for ... health problems in cats     ... the most commonly diagnosed health problems in cats, yet relatively ... until now. Two collaborative studies have been conducted by researchers ...
(Date:11/25/2015)... Orexigen® Therapeutics, Inc. (Nasdaq: OREX ) ... chat discussion at the Piper Jaffray 27th Annual Healthcare ... discussion is scheduled for Wednesday, December 2, at 8:00 ... replay will be available for 14 days after the ... NormartVP, Corporate Communications and Business Development , BrewLife(858) 875-8629 ...
(Date:11/24/2015)... Calif. , Nov. 24, 2015 Cepheid ... will be speaking at the following conference, and invited ... New York, NY      Tuesday, December 1, 2015 ... New York, NY      Tuesday, December 1, 2015 ... Jaffray Healthcare Conference, New York, NY ...
Breaking Biology Technology: