Posts tagged BDNF
Articles and news from the latest research reports.
Research shows why ketamine is an effective antidepressant but memantine is not
Ketamine is a fast-acting antidepressant. However, it can create symptoms that mimic psychosis. Therefore, doctors don’t give it to depressed patients. Memantine, a similar drug, does not have psychotomimetic effects, but it also does not appear to alleviate depression. Lisa M. Monteggia of the University of Texas Southwestern Medical Center and her colleagues have determined that these drugs have different effects on neurotransmitter pathways. In particular, ketamine promotes the expression of neurotrophic factors but memantine doesn’t. The research appears in the Proceedings of the National Academy of Sciences.
Brain study uncovers vital clue in bid to beat epilepsy
People with epilepsy could be helped by new research into the way a key molecule controls brain activity during a seizure.
Researchers have identified the role played by of a protein – called BDNF – and say the discovery could lead to new drugs that calm the symptoms of epileptic seizures.
Scientists analysed the way cells communicate when the brain is most active – such as in epileptic seizures – when electrical signalling by the brain’s neurons is increased.
They found that the BDNF molecule – which is known to be released in the brain during seizures – blocks a specific process known as activity-dependent bulk endocytosis (ABDE).
By blocking this process during an epileptic seizure, BDNF increases the release of neurotransmitters and causes heightened electrical activity in the brain.
Since ADBE is only triggered during high brain activity, drugs designed to target this process could have fewer side effects for normal day to day brain function, researchers say.
Experts say that not all epilepsy patients respond to current drug treatments and the finding could lead to the development of new medicines.
The team, however, offered a word of caution. Since ABDE is also implicated in a range of brain functions, such as creating new memories, more research is needed to establish what the effects of manipulating this molecule might be on these key processes.
The study, led by the University of Edinburgh, is published in the journal Nature Communications. The research was funded by the Wellcome Trust and the Medical Research Council.
Dr Mike Cousin, of the University of Edinburgh’s Centre for Integrative Physiology, who led the research, said: “Around one third of people with epilepsy do not respond to the treatments we currently have available. By studying the way brain cells behave during seizures, we have been able to uncover an exciting new research avenue for research into anti-epileptic therapies.”
Researchers will now focus on identifying specific genes that control this brain process to determine whether they hold the key to new drug treatments.
(Source: eurekalert.org)
Scientists Coax Brain to Regenerate Cells Lost in Huntington’s Disease
Researchers have been able to mobilize the brain’s native stem cells to replenish a type of neuron lost in Huntington’s disease. In the study, which appears today in the journal Cell Stem Cell, the scientists were able to both trigger the production of new neurons in mice with the disease and show that the new cells successfully integrated into the brain’s existing neural networks, dramatically extending the survival of the treated mice.
“This study demonstrates the feasibility of a completely new concept to treat Huntington’s disease, by recruiting the brain’s endogenous neural stem cells to regenerate cells lost to the disease,” said University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., co-director of Rochester’s Center for Translational Neuromedicine.
Huntington’s disease is an inherited neurodegenerative disease characterized by the loss of a specific cell type called the medium spiny neuron, a cell that is critical to motor control. The disease, which affects some 30,000 people in the U.S., results in involuntary movements, problems with coordination, and, ultimately, in cognitive decline and depression. There is currently no way to slow or modify this fatal disease.
For Goldman, the idea behind his strategy to treat the disease emerged from his decades-long study of neural plasticity in canaries. Songbirds like canaries have intrigued biologists because of their ability – unique in the animal kingdom – to lay down new neurons in the adult brain. This process, called adult neurogenesis, was first discovered by Goldman and Fernando Nottebohm of the Rockefeller University in the early 1980s, when the two realized that when learning new songs new neurons were added to regions of the bird’s brain responsible for vocal control.
“Our work with canaries essentially provided us with the information we needed to understand how to add new neurons to adult brain tissue,” said Goldman. “Once we mastered how this happened in birds, we set about how to replicate the process in the adult mammalian brain.”
Humans already possess the ability to create new neurons. Goldman’s lab demonstrated in the 1990s that a font of neuronal precursor cells exist in the lining of the ventricles, structures found in the core of the human brain. In early development, these cells are actively producing neurons. However, shortly after birth the neural stem cells stop generating neurons and instead produce glia, a family of support cells that pervade the central nervous system. Some parts of the human brain continue to produce neurons into adulthood, the most prominent example is the hippocampus where memories are formed and stored. But in the striatum, the region of the brain that is devastated by Huntington’s disease, this capability is “switched off” in adulthood.
Goldman and his team spent the past decade attempting to unravel the precise chemical signaling responsible for instructing neural stem cells when to create neurons and when to create glia cells. One of the most critical clues came directly from the earlier research with canaries. In the part of the bird’s brain were new songs are acquired and neurons added, the scientists observed the regulated expression of a protein called brain derived neurotrophic factor, or BDNF. When the production of this protein is triggered, the local neural stem cells are instructed to produce neurons.
At the same time, the scientists also realized that they had to simultaneously suppress the bias of these stem cells to produce glia. They found that when BDNF was combined with another molecule called noggin – a protein that inhibits the chemical pathway that dictates the creation of glial cells – they could successfully switch the stem cell’s molecular machinery over to the production of neurons.
The next challenge was how to deliver these two proteins – BDNF and noggin – precisely and in a sustained fashion to the area of the brain involved in Huntington’s disease. To do so, they partnered with scientists at the University of Iowa to modify a viral gene therapeutic, called an adeno-associated virus, to deliver the necessary molecular instructions to the neural stem cells.
The virus infected the target cells in the brains of mice with Huntington’s disease and triggered the sustained over-expression of both BDNF and noggin. This, in turn, activated the neighboring neural stem cells which began to produce medium spiny motor neurons. The new neurons were continuously generated and migrated to the striatum, the region of the brain impacted by Huntington’s disease, where they then integrated into the existing neuronal networks.
The researchers were able to significantly extend the survival of the treated mice, in some cases doubling their life expectancy. The researchers also devised a way to tag the new neurons and observed that the cells extended fibers to distant targets within the brain and establish electrical communication.
After having established the ability to generate new replacement neurons in mouse models of Huntington’s disease, the researchers also demonstrated that they could replicate this technique in the brains of normal squirrel monkeys, a step that brings the research much closer to tests in humans.
“The sustained delivery of BDNF and noggin into the adult brain was clearly associated with both increased neurogenesis and delayed disease progression,” said Goldman. “We believe that our data suggest the feasibility of this process as a viable therapeutic strategy for Huntington’s disease.”
Vitamin P as a potential approach for the treatment of damaged motor neurons
Biologists from the Ruhr-Universität Bochum have explored how to protect neurons that control movements from dying off. In the journal “Molecular and Cellular Neuroscience” they report that the molecule 7,8-Dihydroxyflavone, also known as vitamin P, ensures the survival of motor neurons in culture. It sends the survival signal on another path than the molecule Brain Derived Neurotrophic Factor (BDNF), which was previously considered a candidate for the treatment of motoneuron diseases or after spinal cord damage. “The Brain Derived Neurotrophic Factor only had a limited effect when tested on humans, and even had partially negative consequences”, says Prof. Dr. Stefan Wiese from the RUB Work Group for Molecular Cell Biology. “Therefore we are looking for alternative ways to find new approaches for the treatment of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.”
Same effect, different mode of action
In previous studies, researchers hypothesised that vitamin P is an analogue of BDNF and thus works in the same way. This theory has been disproved by the team led by Dr. Teresa Tsai and Prof. Stefan Wiese from the Group for Molecular Cell Biology and the Department of Cell Morphology and Molecular Neurobiology headed by Prof. Andreas Faissner. Both substances ensure that isolated motor neurons of the mouse survive in cell culture and grow new processes, but what exactly the molecules trigger at the protein level varies. BDNF activates two signalling pathways, the so-called MAP kinase and PI3K/AKT signal paths. Vitamin P on the other hand makes use only of the latter.
The dose is crucial
However, vitamin P only unfolded its positive effects on the motor neurons in a very small concentration range. “These results show how important an accurate determination of dose and effect is”, says Prof. Wiese. An overdose of vitamin P reduced the survival effect, and over a certain amount, no more positive effects occurred at all. The researchers hope that vitamin P could have less negative side effects than BDNF. “It is easier to use, because vitamin P, in contrast to BDNF, can pass the blood-brain barrier and therefore does not have to be introduced into the cerebrospinal fluid using pumps like BDNF,” says Wiese.
Morphine and cocaine affect reward sensation differently
A new study by scientists in the US has found that the opiate morphine and the stimulant cocaine act on the reward centers in the brain in different ways, contradicting previous theories that these types of drugs acted in the same way.
Morphine and cocaine both affect the flow of the neurotransmitter dopamine, which has been shown to be important in the feeling of reward. When a dopamine neuron is stimulated it releases dopamine, which is then taken up by neighboring cells. Any excess is reabsorbed into the original dopamine neuron by a process known as “reuptake.”
Cocaine is known to block reuptake, and the excess dopamine leads to an enhanced reward effect. Cocaine is also known to make the cells in the nucleus accumbens, which receives signals from the VTA, more sensitive to cocaine. It was already known a protein called brain-derived neurotrophic factor (BDNF) in the VTA region of the brain enhances the reward response to cocaine.
The new study shows that BDNF has the opposite effect when morphine is present, decreasing the reward response and the development of addiction rather than enhancing it. The researchers identified numerous genes regulated by BDNF and associated with its effects. They used genetic techniques to suppress BDNF, and then directly excited the neurons in the nucleus accumbens that normally receives transmitted impulses from the VTA.
They found that suppressing BDNF in the VTA allowed morphine to increase the excitability of dopamine neurons and hence enhance the reward. When they optically excited the dopamine terminals in the nucleus accumbens that normally receive the transmissions from the VTA, they also found a reversal in the normal effect of BDNF.