A1R

Parkinson's disease affects 3% of population over 65 years old, and the average age of onset is 60. Regarding juvenile Parkinson, which represents the rest of all Parkison's cases, the disease begins before 40 years old. Now, a group of researchers has deciphered the molecular mechanism by which a mutation of the adenosine type 1 receptor gene is associated with juvenile Parkinson's. Parkinson's disease affects 3% of population over 65 years old, and the average age of onset is 60. Regarding juvenile Parkinson, which represents the of all Parkison's cases, the disease begins before 40 years old. Now, a group of researchers of the Faculty of Medicine and Health Sciences, the Institute of Neurosciences of the University of Barcelona (UBNeuro) and the Bellvitge Biomedical Research Institute (IDIBELL), has deciphered, for the first time, the molecular mechanism by which a mutation of the adenosine type 1 receptor gene is associated with juvenile Parkinson's. The team, led by Professor Francisco Ciruela (UB-IDIBELL-UBNeuro), focused on the study of the mechanistic field of the mutation of the brain receptor, previously defined as the potential cause for the early disease. The results, presented in the journal Biomedicine and Pharmacotherapy, reveal that the mutation reduced this receptor's ability to interact with other adenosine receptors -- with the type 2receptor -- , which would cause an increase in the neuronal circuits' excitability in the brain region called the striatum. "We propose that the inability of both adenosine receptors to interact would generate glutamatergic hyperexcitability in the neuronal circuits of the striatum, a key mechanism in the pathogenesis of juvenile Parkinson's," notes Francisco Ciruela, professor of the Department of Pathology and Experimental Therapeutics of the UB and head of the IDIBELL Research Group on Neuropharmacology and Pain. An imbalance in the excitability of the neuronal circuit The adenosine receptors are brain receptors assembled to G proteins and involved in motor functions. Previously, their involvement in neurodegenerative pathologies such as Parkinson's disease had already been suggested. The studied mutation affects the type 1 adenosine receptor, which has an inhibitory effect on its counterpart -- the type 2 adenosine receptor -- through which it facilitates the glutamate release and the circuit's excitability. According to the conclusions, the mutation would prevent the molecular and functional interaction of both adenosine receptors and, as a result, it would facilitate glutamate release, which would cause hyperexcitability in the striatum neuronal circuits. The study includes the participation of research teams from the Autonomous University of Barcelona (UAB), the Luxembourg Institute of Health (LIH) and the National Institutes of Health (NIH) in Baltimore (United States).

A new peptide administered through a nasal spray shows promising results as an anticonvulsant and could ultimately be further developed as a treatment to prevent seizures in both epilepsy and Alzheimer’s disease (AD). A study published in The American Society for Clinical Investigation outlines work conducted by researchers to develop a peptide called A1R-CT that disrupts the signaling between the molecule neurabin and the adenosine 1 receptor (A1R). A1R sits on the outside of the neuron and responds to adenosine, whereas neurabin binds to the receptor and blocks it from use. It has previously been established that A1R has neuroprotective effects and that, when activated by adenosine, it mediates an anti-convulsant response. This, however, is often blocked by neurabin. “Neurabin is a brake, so it doesn’t do too much,” Dr. Qin Wang, neuropharmacologist and founding director of the program for Alzheimer's therapeutics discovery at the Medical College of Georgia at Augusta University, told Science News. “But now we need to remove it to unleash A1’s power." It is a balancing act, though. While activating the receptor allows for A1R to be used as an anti-convulsant, “the A1 receptor itself has to be regulated because if it's activated too much, you will fall asleep,” Wang explained. To further investigate the effect of A1R and neurabin, the researchers experimentally blocked the A1R receptor in neurabin-deficient mice. These mice experienced more severe seizures, and the death rate increased by more than 50%. They found that the mice that had a natural neurabin deficiency had significantly shorter and less severe seizures, and they all survived, whereas the mice with normal neurabin levels had worse seizures, and about 10% of them died shortly after. After establishing this activity in mice, the researchers concluded that the A1R-CT peptide disrupts the neurabin-A1R interaction and allows A1R to work as an anti-convulsant and elicit an anti-seizure response. Epileptic seizures are common after brain injury, stroke and with chronic neurological diseases such as AD. In fact, up to 64% of individuals who suffer from AD experience seizures. These seizures vary in length and severity, but two types are more common than others: tonic-clonic seizures, during which the patient falls down, shakes and becomes unresponsive and focal onset, during which the patient experiences repetitive arm or leg movements, lip smacking and chewing. There is an urgent need for novel therapies as seizures are uncontrolled by current medications and techniques in about 40% of people who experience them. When these seizures are left uncontrolled and untreated they often lead to brain damage and cognitive impairment. When testing the A1R-CT peptide, the researchers found a dramatic decrease in neuron death in the Alzheimer’s model as well as an improvement in the severity, duration and death rate. The peptide was effective both as an injection and as a nasal spray. The team’s next steps will be to work out dosing and tweaking the peptide so it can function optimally and, perhaps one day, be used as a rescue treatment for human patients suffering chronic seizures.

A novel peptide augments the brain's natural mechanism to help prevent seizures and protect neurons in research models of both Alzheimer's and epilepsy, scientists report. A novel peptide augments the brain's natural mechanism to help prevent seizures and protect neurons in research models of both Alzheimer's and epilepsy, scientists report. The A1R-CT peptide the scientists developed, which can be administered through a nasal spray, holds promise for tamping down the uncontrolled electrical activity that is common after traumatic brain injury, stroke and which affects more than half of individuals with Alzheimer's, says Dr. Qin Wang, neuropharmacologist and founding director of the Program for Alzheimer's Therapeutics Discovery at the Medical College of Georgia at Augusta University. The fact that it can be delivered through the nose indicates the peptide's potential as a new seizure rescue medication as well, to help interrupt, for example, a seizure cluster, where disabling seizures are occurring back-to- back, says Wang, corresponding author of the study in the journal JCI Insight. A1R-CT works by inhibiting neurabin, a protein that helps ensure that the protective mechanism itself, which tamps down the hyperexcitability of neurons that disrupts normal communication and produces seizures, doesn't overdo, she says. The peptide was named after the protective adenosine 1 receptor on the surface of neurons, which gets activated by adenosine, a chemical made mostly in the brain by neuron-supporting glial cells in response to hyperexcitability. "This is a powerful receptor to then silence the neurons," Wang says. This natural, calming relationship also is known to block electrical activity that can result in an irregular heartbeat. In fact, an injectable form of adenosine is used to treat a very high heart rate. "But the A1 receptor itself has to be regulated because if it's activated too much, you will fall asleep," says Wang. "The neurons try to make sure everything stays in control and in most of us, it works pretty well. We don't fall asleep at our desk. We don't have seizures," she says, noting that caffeine blocks the A1 receptor. Alzheimer's often is accompanied by seizures because the characteristic buildup of the proteins amyloid and tau in the brain disrupts communication between neurons, creates increased oxidative stress and resulting inflammation, and in response to the altered dynamic, neurons can become hyperexcited, she says. "In Alzheimer's there are so many things that go wrong," she says. Seizures can precede the cognitive decline in Alzheimer's, and definitely contribute to it, Wang says. A1 receptor's activation by adenosine in this type of hyperactive scenario makes it seem like a logical treatment target for seizures. But the fact that it is so pervasive throughout the body, including in the heart, lungs and kidneys, makes potential extensive side effects likely. Back to neurons' desire for homeostasis, Wang and her colleagues were the ones who found that the protein neurabin, which appears to be primarily present in the brain, provides that balance to prevent hyperactivity of the A1 receptor. The fact neurabin is primarily in the brain, means that altering its activity should not have the potential body-wide impact of directly altering A1 receptor activity, Wang says. "Neurabin is a brake so it doesn't do too much," Wang says. "But now we need to remove it to unleash A1's power." So, they set to work developing the peptide that could instead interfere with the A1 receptor and neurabin's interaction and so enable more of the natural protective, seizure-reducing benefit. A1 receptor activation tamps down the excited state of the neurons by modulating ion channels -- proteins in the cell membrane that allow passage through the cell of other proteins -- which help generate electrical signals. A result is so-called hyperpolarization, which means the neuron is less likely to fire an electrical signal. "The more polarized the neurons are, the harder it is for them to get excited," Wang says. A1 receptor activation also decreases the release of glutamate, a neurotransmitter produced by neurons that excites neurons. It also provides additional benefit to neurons by providing some protection from inadequate oxygen and blood supplies, which may occur in the case of an injury. The scientists have noted a dramatic reduction in death of neurons in their Alzheimer's model, for example, with the use of their peptide. Now they've shown that inhibiting neurabin -- either by reducing it directly or with their peptide -- enables increased action by A1C to reduce excessive electrical activity in the brain. They've shown the peptide is effective in both a mouse model of severe seizures and seizures in an Alzheimer's mouse model. And It's effective when directly injected into the brain or via nasal spray. The scientists opted to look at nasal spray delivery to fully explore the peptide's potential clinical benefit. They found a similar robust response in both the seizure and Alzheimer's models. Looking further at the impact of targeting neurabin, they found that mice with a neurabin deficiency had significantly shorter, less severe seizures and they all survived. Those with the normal neurabin levels intact experienced seizures lasting for up to 30 minutes and about 10% of the mice died shortly afterward. Blocking A1 receptor resulted in more severe seizures in the neurabin-deficient mice and increased the death rate to more than 50%. Next steps include additional exploration of ideal doses and delivery times for specific conditions the peptide may be used to treat. The scientific team also continues to tweak the peptide to ensure it functions optimally, and is pursuing funding needed to pursue clinical trials. Wang, a Georgia Research Alliance Eminent Scholar, came to MCG in April 2021 from the University of Alabama at Birmingham, where she began the studies of A1 receptor and peptide development. She continues extensive collaboration with her colleagues at UAB on the studies who are coauthors on the new paper. First author Dr. Shalini Saggu is now also a faculty member in the MCG Department of Neuroscience and Regenerative Medicine. Epileptic seizures are common after a traumatic brain injury; a stroke, which is considered an acquired brain injury; and with chronic neurodegenerative diseases including Alzheimer's. As much as 64% of the some 50 million individuals with Alzheimer's experience seizures, the scientists write. Patients can experience generalized tonic-clonic seizures, in which they fall down, shake and become unresponsive. Also, focal onset seizure, which tend to be shorter and may include repetitive movement of the arms or legs, lip smacking and chewing. Seizures are uncontrolled in about 40% of people, which indicates an urgent need for novel therapies, the scientists write, and current therapies tend to be less effective in individuals with Alzheimer's. Left uncontrolled, seizures can produce brain damage and cognitive impairment. Adenosine also is a building block of our DNA and a component of the cell fuel ATP. The research was supported by the National Institutes of Health.