Tag Archives: neurotransmitter acetylcholine

New asthma treatment

A new treatment could prevent delayed asthma attacks, which can occur several hours after exposure to allergens, a study showed today.

Research led by scientists from Imperial College London could explain why around half of people with asthma experience a “late phase” of symptoms.

Scientists found that blocking sensory nerve functions stopped a “late asthmatic response” in mice and rats.

The findings, published in the journal Thorax, could lead to better treatments for the disease, researchers said.

An estimated 300 million people suffer from asthma. Symptoms are commonly triggered by allergens in the environment, such as pollen and dust mites, and these stimuli can cause the airways to tighten within minutes, causing breathing difficulties.

Many sufferers also experience a “late asthmatic response” three to eight hours after exposure to allergens, causing breathing difficulties which can last up to 24 hours.

When sufferers have an “early response”, the allergen is recognised by mast cells, which release chemical signals that cause the airways to narrow.

The mechanism behind the late phase has remained unclear but, in new research on mice and rats, scientists found evidence that the late asthmatic response happens because the allergen triggers sensory nerves in the airways.

Asthma

Asthma

These nerves activate reflexes which trigger other nerves that release the neurotransmitter acetylcholine, which causes the airways to narrow.

Scientists claim that if the findings translate to humans, it would mean that drugs which block acetylcholine – called anticholinergics – could be used to treat asthma patients who experience late phase responses.

At present steroids are the main treatments prescribed for asthma, but they are not effective for all patients.

A recent clinical trial involving 210 asthma patients found that the anticholinergic drug tiotropium improved symptoms when added to a steroid inhaler, but the reason for this was unexplained.

Professor Maria Belvisi, from the National Heart and Lung Institute at Imperial College London, who led the research, said: “Many asthmatics have symptoms at night after exposure to allergens during the day, but until now we haven’t understood how this late response is brought about.

“Our study in animals suggests that anticholinergic drugs might help to alleviate these symptoms, and this is supported by the recent clinical data.


“We are seeking funding to see if these findings are reproduced in proof of concept clinical studies in asthmatics.”

Professor Stephen Holgate, funding board chair for the Medical Research Council, which funded the study, said: “Unravelling the complex biology of asthma is vitally important, as it is an extremely dangerous condition which exerts lifelong damaging effects.

“The Medical Research Council is committed to research that opens doors to improving disease resilience, particularly in conditions which attack our body over the long term.

“Studies like this are making really important progress and, whilst we must always be cautious when taking findings from rodents into humans, these are very interesting and potentially important results.”

Dr Samantha Walker, director of research and policy at Asthma UK, said: “This research seeks to understand the causes of chronic asthma symptoms and may pave the way for identifying new treatments for people with asthma in the future.”

High fat cholesterol diet damages brain

Research from the Laboratory of Psychiatry and Experimental Alzheimers Research at the Medical University Innsbruck (Austria) demonstrated that chronic high fat cholesterol diet in rats exhibited pathologies similar to Alzheimer’s disease.

The results were published in Molecular Cellular Neuroscience with lead author Dr. Christian Humpel. The study was co-authored by PhD students, Celine Ullrich and Michael Pirchl, from the same Laboratory.

Alzheimer’s disease is a severe neurodegenerative disorder of the brain that is characterized by loss of memory and cognitive decline. The majority of Alzheimer’s disease cases are sporadic (risk age >60 years), and only <2.5% have a genetic disposition. It is estimated that in 2050, approximately 80 million people will suffer from Alzheimer's disease worldwide. The major pathological hallmarks of Alzheimer's disease are extracellular aggregates (plaques) of the small peptide beta-amyloid, hyperphosphorylation of the protein tau and subsequent formation of intracellular neurofibrillary tangles, degeneration of neurons secreting the neurotransmitter acetylcholine, inflammation, and cerebrovascular dysfunction.

Alzheimer's

Alzheimer's

The causes for Alzheimer’s disease are not known, but dysregulation of amyloid-precursor protein expression and beta-amyloid clearance is hypothesized (beta-amyloid cascade). Alternatively, a pathological cascade of events may trigger hyper-phosphorylation of tau, putting the tau-hypothesis into the center. A third hypothesis suggests that chronic long-lasting mild cerebrovascular damage, including inflammatory processes and oxidative stress, may cause Alzheimer’s disease. It has been suggested that Alzheimer’s disease starts 20-30 years before first symptoms appear and recent studies have shown, that high cholesterol levels are linked to the pathology of this disease.


The aim of the study led by Humpel was to study the effects of hypercholesterolemia in adult rats. Male 6 months old Sprague Dawley rats were fed with normal food (controls) or with a special 5% cholesterol-enriched diet (hypercholesterolemia). After 5 months animals were tested for behavioral impairments and pathological markers similar to those found in the brains of patients with Alzheimer’s disease. The results showed that chronic hypercholesterolemia caused memory impairment, cholinergic dysfunction, inflammation, enhanced cortical beta-amyloid and tau and induced microbleedings, all indications, which resemble an Alzheimer’s disease-like pathology.

Thus the data are in line with earlier studies showing that high fat lipids, including cholesterol, may participate in the development of sporadic Alzheimer’s disease. However, since Alzheimer’s disease is a complex heterogenous disease, these data do not allow the conclusion that cholesterol alone is responsible for the disease. It can be speculated that chronic mild cerebrovascular damage caused and potentiated by different vascular risk factors (including cholesterol) may contribute to these pathologies. It needs to be determined in future studies how mild chronic microvascular bleedings, silent strokes and mild blood-brain barrier damage over decades may play a role in the development of this disease. Indeed several data (Ladecola, Nat.Rev.Neurosci. 5, 347-360, 2004) support the view that Alzheimer’s disease can be considered as a vascular disease and that a dysfunctional clearance of beta-amyloid from brain to blood and vice versa may be a secondary important step in the cascade of initiation of the disease.

This study was supported by the Austrian Science Funds (P19122-B05).