Recent research suggests a method by which excessive dopamine can lead to addiction, and too little dopamine can cause freezing in Parkinson’s disease patients.
By investigating the strength of synapses connecting the cerebral cortex to the striatum, researchers at the Feinberg School of Medicine at Northwestern University (IL, USA) have identified ways in which dopamine contributes to addiction as well as to freezing in Parkinson’s disease (PD) patients. Two circuits within the striatum, the ‘stop’ and ‘go’ circuits, determine whether a desire is acted on or not.
“The study shows how dopamine shapes the two main circuits of the brain that control how we choose to act and what happens in these disease states,” explained D James Surmeier, lead author of the study.
The researchers activated cortical fibers to simulate movement commands and increased the natural levels of dopamine present. This resulted in a strengthening of synapses in the ‘go’ circuit and a weakening in the ‘stop’ circuit synapses.
“This could be what underlies addiction,” Surmeier continued. “Dopamine released by drugs leads to abnormal strengthening of the cortical synapses driving the striatal ‘go’ circuits, while weakening synapses at opposing ‘stop’ circuits. As a result, when events associated with drug taking (e.g., where you took the drug, what you were feeling etc.) occur, there is an uncontrollable drive to go and seek drugs.”
“All of our actions in a healthy brain are balanced by the urge to do something and the urge to stop,” Surmeier said. “Our work suggests that it is not just the strengthening of the brain circuits helping select actions that is critical to dopamine’s effects, it is the weakening of the connections that enable us to stop as well.”
In addition, the group simulated cortical movement commands in dopamine receptor transgenic mice, an animal model of PD, and found that in this situation the stop circuit synapses were strengthened and those in the go circuit were weakened.
“The study illuminates why PD patients have trouble performing everyday tasks like reaching across a table to pick up a glass of water when they are thirsty,” Surmeier commented. “Our study suggests that the inability to move in PD is not a passive process, like a car running out of gas. Rather, the car doesn’t move because your foot is jammed down on the brake. Dopamine normally helps you adjust the pressure on the brake and gas pedals. It helps you learn that when you see a red light at an intersection, you brake and when the green light comes on, you take your foot off the brake and depress the gas pedal to go. PD patients, who have lost the neurons that release dopamine, have their foot perpetually stuck on the brake.”
Source: Shen W, Flajolet M, Greengard P, Surmeier DJ. Dichotomous dopaminergic control of striatal synaptic plasticity. Science 321(5890), 848–851 (2008).
MP-470 granted orphan drug designation
Orphan drug designation was granted recently by the US FDA for SuperGen Inc.’s tyrosine kinase inhibitor, MP-470, for the treatment of glioblastoma multiforme.
MP-470 has been given this designation, which is given to products that demonstrate promise for the diagnosis and/or treatment of rare diseases that affect fewer than 200,000 people in the USA, based on positive results from in vitro studies in glioblastoma multiforme (GBM) cell lines. It was demonstrated that MP-470 or ionizing radiation alone induced cell death, but when used in combination, cell death was more than doubled.
MP-470 is currently in Phase I trials as both a single agent and in combination with chemotherapy for the treatment of patients with solid tumors. A Phase Ib study in patients with GBM is planned.
“GBM is the most common malignant primary brain tumor, representing approximately 10% of all brain tumors,” said Gregory Berk, SuperGen’s Chief Medical Officer. “This designation not only underscores the need for improved therapies in GBM, it also underscores the company’s development strategy in pursuing areas of unmet need.”
Source: SuperGen Inc. Press Release: SuperGen granted orphan drug designation for MP-470 in glioblastoma multiforme. www.supergen.com
Women with schizophrenia may benefit from estrogen treatment
Researchers from Monash University (Melbourne, Australia) have demonstrated beneficial effects of transdermal estradiol on women with schizophrenia.
A total of 102 women of childbearing age with schizophrenia were randomized to receive either 100 µg transdermal estradiol (n = 56) or placebo (n = 46) as an adjunct to their usual antipsychotic medication for 28 days. Psychological symptoms were assessed weekly using the Positive and Negative Syndrome Scale.
Those treated with transdermal estradiol experienced an improvement in psychotic symptoms in addition to a reduction in positive symptoms of schizophrenia. There was no change in negative symptoms between those receiving estradiol and schizophrenia.
“Estrogen treatment is a promising new area for future treatment of schizophrenia and potentially for other severe mental illnesses,” commented first author Jayashri Kulkarni. “There is a lot to be done. But I believe that we have opened up a new and promising area of treatment for a debilitating illness in both women and men.”
Source: Kulkarni J, de Castella A, Fitzgerald PB et al. Estrogen in severe mental illness: a potential new treatment approach. Arch. Gen. Psychiatry 65(8), 955–960 (2008).
Potential of antihypertensive drugs for the prevention and treatment of Alzheimer’s disease
Study finds angiotensin receptor blockers successful in preventing the development and progression of Alzheimer’s disease.
Research presented recently at the International Conference on Alzheimer’s Disease (AD) in Chicago (IL, USA) has identified a promising new agent for AD: angiotensin receptor blockers (ARBs). Data were analyzed from approximately 6 million patients aged 65 years or older (median: 75 years; 98% of whom were male, treated for high blood pressure between 2002 and 2006. The patients were grouped into those receiving ARBs, angiotensin-converting enzyme inhibitors and other cardiovascular medicines.
Patients who were taking ARBs were 35–40% less likely to develop AD or other forms of dementia than patients on the other medications. In addition, patients who were already suffering from AD were 45% less likely to develop delirium, be admitted to a nursing home or to die prematurely if they had been taking ARBs compared with the other medications.
Study leader Benjamin Wolozin commented, “For those who already have dementia, use of ARBs might delay deterioration of brain function and help keep patients out of nursing homes… The study is particularly interesting because we compared the effects of ARBs to other medications used for treating blood pressure or cardiovascular disease.”
Approximately 4.5 million Americans are affected by AD, and this number will only increase as the average age of the population increases. Indeed, the number of people suffering from the disease is expected to have tripled by 2050. Given this ever-increasing prevalence of AD, effective methods of prevention and treatment of the disorder are critically needed.
Clive Ballard of the Alzheimer’s Society commented, “High blood pressure doubles risk of AD and increases risk of stroke. This study highlights that it is becoming increasingly important to investigate antihypertension drugs as a potential treatment for dementia… A proper clinical trial is now needed to investigate if this particular class of drug can benefit thousands of people living with this devastating condition.”
Source: Wolozin B, Lee A, Lee A, Whitmer R, Kazis L. Use of angiotensin receptor blockers is associated with a lower incidence and progression of Alzheimer disease. ICAD (2008 ) (Abstract O1-05-05).
Promising data released on new oral treatment for MS sufferers
Phase II clinical trial data published recently in The Lancet have revealed the potential benefits of laquinimod in the treatment of multiple sclerosis (MS). The study involved 306 adult patients from 51 centers in nine countries, who were selected if they had experienced at least one relapse in the year prior to the beginning of the trial and at least one gadolinium-enhancing lesion as detected by MRI screening. The results showed that oral laquinimod induced a 40.4% decrease in the number of gadolinium-enhancing lesions in patients over the last four scans versus baseline figures.
The authors stated that: “Overall, the efficacy and safety profile emerging from this, and from a previous Phase II clinical trial, in combination with the oral route of administration, make laquinimod a promising therapeutic opportunity for patients with relapse–remitting MS. The benefits and risks of laquinimod treatment are now being further assessed in a large-scale Phase III trial.”
MS is an immune disorder of the CNS which causes the myelin sheath surrounding neurons in the white matter of the brain to degrade, and can result in potentially debilitating manifestations, such as partial or complete paralysis and loss of vision. Previous treatments have historically adopted infusion or injection methods of administration, and it is believed that the development of an oral therapy could significantly improve the quality of life of MS patients.
Source: Comi G, Pulizzi A, Rovaris M et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled Phase IIb study. Lancet 371(9630), 2085–2092 (2008); comment, 2059–2060 (2008).
Gastrointestinal bleeding associated with worse outcomes in stroke sufferers
A study published online recently in the journal Neurology, has found that patients with ischemic stroke who also experience gastrointestinal (GI) bleeding are more likely to die during their hospital stay or be heavily dependent on others for their care once discharged than those without GI bleeding.
“This is an important finding since there are effective medications to reduce gastric acid that can lead to upper GI bleeding,” commented study author Martin O’Donnell, of McMaster University (ON, Canada). “More research will be needed to determine whether this is a viable strategy to improve outcomes after stroke in high-risk patients.”
A total of 6853 patients who have suffered an ischemic stroke and have been admitted to one of 11 Ontario hospitals between 2003 and 2006 were included in the study. Of those patients, 829 died during their hospital stay and 1374 died within the 6 months following the stroke.
A total of 100 patients (1.5%) experienced GI bleeding during hospitalization. These patients were found to be three-times more likely to die during their hospital stay or be heavily dependent on others at the time they left hospital (81% compared with 41% of patients who had not experienced GI bleeding). In addition, those with GI bleeding were 1.5-times more likely to have died in the 6 months following the stroke than those without (46% compared with 20%, respectively).
“One of the key points we want to raise is that people are generally prone to developing medical complications with stroke,” explained O’Donnell, “And as part of that larger observation, we know that among these complications are GI issues… And We feel that this is particularly important, because GI bleeding is a complication that is potentially modifiable with various treatment strategies.”
Source: O’Donnell MJ, Kapral MK, Fang J et al. Gastrointestinal bleeding after acute ischemic stroke. Neurology (2008) (Epub ahead of print).
Rember™ shows promising results in Phase II trials
Drug: Rember™
Maufacturer: TauRx Therapeutics
Indication: Alzheimer’s disease
A Phase II clinical trial conducted in Singapore and the UK has produced encouraging results that methylthioninium chloride (MTC) could be used in the treatment of Alzheimer’s disease. The results of the study carried out by TauRx Therapeutics were announced at the Alzheimer’s Association International Conference on Alzheimer’s Disease. They showed a reduction in the cognitive decline of moderate sufferers over a 24-week period and a reduction in decline of mild sufferers over a 50-week period, when compared with a control group receiving a placebo for the first 24 weeks and a low dose of MTC for the remaining weeks.
It has been suggested that MTC causes a slowing in disease progression by reducing tangles between tau protein filaments in the brain cells. The MTC compound used in the trial is being patented by TauRX for Alzheimer’s treatment as Rember™. TauRx are proceeding to a Phase III trial with Rember and are also testing its effectiveness in treating Parkinson’s disease due to its targeting of synuclein fibers, which are found in the brains of Parkinson’s sufferers.
Source: Alzheimer’s Association International Conference on Alzheimer’s Disease 2008 www.alz.org/icad; TauRx Therapeutics Ltd www.taurx.com