Summary: A1R-CT, a novel peptide that binds to neurabin, can be administered via a nasal spray and has the potential to interrupt the uncontrollable brain activity associated with TBI, stroke, epilepsy and Alzheimer’s disease.
Source: Medical School of Georgia at Augusta University
A new peptide boosts 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 via a nasal spray, shows promise in reducing the uncontrolled electrical activity that is common after traumatic brain injury, stroke, and affects more than half of people with Alzheimer’s, says Dr. Qin Wang, neuropharmacologist and founding director of the Alzheimer’s Therapeutics Discovery Program at the Medical College of Georgia at Augusta University.
The fact that it can be delivered through the nose also indicates the peptide’s potential as a new seizure rescue drug, to help interrupt, for example, a cluster of seizures, where incapacitating seizures occur back-to-back, says Wang, corresponding author. from the study to the magazine JCI Insight.
A1R-CT works by inhibiting neurabin, a protein that helps ensure that the protective mechanism itself, which reduces the hyperexcitability of neurons that disrupts normal communication and produces seizures, doesn’t go into overdrive, he says.
The peptide was named after the protective adenosine receptor 1 on the surface of neurons, which is activated by adenosine, a chemical made primarily in the brain by glial cells that support neurons in response to hyperexcitability
“This is a powerful receptor for silencing neurons,” says Wang. This natural, calming relationship is also known to block electrical activity that can cause 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’ll fall asleep,” says Wang. “Neurons try to make sure everything is under control and in most of us, it works pretty well. We don’t fall asleep at our desk. We don’t have seizures,” he says, noting that caffeine blocks the A1 receptor.
Alzheimer’s is often accompanied by seizures because the characteristic accumulation of amyloid and tau proteins in the brain disrupts communication between neurons, creates increased oxidative stress and resulting inflammation, and, in response to the altered dynamics, neurons can be hyperexcited, he says.
“There are so many things that go wrong in Alzheimer’s,” he says. Seizures may precede and definitely contribute to cognitive decline in Alzheimer’s, Wang says.
A1 receptor activation by adenosine in this type of hyperactive setting makes it seem like a logical treatment target for seizures. But the fact that it is so widespread throughout the body, including the heart, lungs and kidneys, makes extensive side effects possible.
Returning to neurons’ desire for homeostasis, Wang and his colleagues were the first to find that the protein neurabin, which appears to be present primarily in the brain, provides this balance to prevent A1 receptor hyperactivity.
The fact that neurabin is primarily in the brain means that altering its activity should not have the potential impact throughout the body of directly altering A1 receptor activity, Wang says.
“Neurabin is a brake, so it doesn’t do too much,” says Wang. “But now we have to remove it to release the power of the A1.”
So they set to work developing the peptide that could interfere with the A1 receptor and neurabin interaction and thus allow for more of the natural protective benefits that reduce seizures.
Activation of the A1 receptor reduces the excited state of neurons by modulating ion channels (cell membrane proteins that allow other proteins to pass through the cell) that help generate electrical signals.
The 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,” says Wang.
Activation of the A1 receptor also decreases the release of glutamate, a neurotransmitter produced by neurons that excites neurons. It also provides additional benefits to neurons by providing some protection against inadequate oxygen and blood supplies, which can occur in the event of injury. Scientists have seen a dramatic reduction in neuron death in their Alzheimer’s model, for example, with the use of their peptide.
Now they have shown that inhibiting neurabin, either by reducing it directly or with its peptide, increases the action of A1C to reduce excessive electrical activity in the brain. They have shown that the peptide is effective in both a mouse model of severe seizures and a mouse model of Alzheimer’s. And it is effective when injected directly into the brain or via nasal spray.
The scientists chose to look at nasal spray delivery to fully explore the potential clinical benefit of the peptide. They found a similar robust response in both the seizure and Alzheimer’s models.
Looking further into the impact of targeting neurabin, they found that neurabin-deficient mice had significantly shorter and less severe seizures, and all survived. Those with normal levels of neurabin intact experienced seizures that lasted up to 30 minutes, and about 10% of the mice died soon after.
Blockade of the A1 receptor caused more severe seizures in the neurabin-deficient mice and increased the death rate to more than 50%.
Next steps include further exploration of ideal doses and delivery times for specific conditions for which the peptide can be treated.
The scientific team is also continuing to fine-tune the peptide to ensure it works optimally and is seeking funding to conduct clinical trials.
Wang, a Georgia Research Alliance Distinguished Fellow, came to MCG in April 2021 from the University of Alabama at Birmingham, where she began studies on A1 receptor and peptide development. He continues an extensive collaboration with his colleagues from the UAB in the studies that are co-authors of the new work. The first author, Dr. Shalini Saggu, is now also a faculty member in the Department of Neuroscience and Regenerative Medicine at MCG.
Epileptic seizures are common after traumatic brain injury; a stroke, which is considered an acquired brain injury; and with chronic neurodegenerative diseases including Alzheimer’s.
Up to 64% of the estimated 50 million people with Alzheimer’s experience seizures, the scientists write. Patients may experience generalized tonic-clonic seizures, in which they fall, shake, and become unresponsive. Also, focal-onset seizures, which are usually shorter and may include repetitive arm or leg movements, lip smacking, and chewing.
Seizures are not controlled in about 40 percent of people, indicating an urgent need for new therapies, the scientists write, and current therapies tend to be less effective in people with Alzheimer’s. If left unchecked, seizures can lead to brain damage and cognitive impairment.
Adenosine is also a building block of our DNA and a component of the cellular fuel ATP.
Funding: The research was supported by the National Institutes of Health.
About this neuropharmacology research news
Author: Tony Baker
Source: Medical School of Georgia at Augusta University
Contact: Toni Baker – Medical School of Georgia at Augusta University
Image: The image is in the public domain
Original Research: Open access
“A Peptide Blocking ADORA1-Neurabin Interaction Is Anticonvulsant and Inhibits Epilepsy in an Alzheimer’s Model” by Qin Wang et al. JCI Insights
A peptide that blocks the ADORA1-neurabin interaction is anticonvulsant and inhibits epilepsy in an Alzheimer’s model
Epileptic seizures are common sequelae of stroke, acute brain injury, and chronic neurodegenerative diseases, including Alzheimer’s disease (AD), and cannot be effectively controlled in approximately 40% of patients, requiring the development of new therapeutic agents.
Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism to self-terminate seizures and protect neurons from excitotoxicity. However, targeting the A1R for neurological disorders has been hampered by side effects associated with its broad expression outside the nervous system.
Here we aim to target the A1R/neurabin/signaling-specific G protein regulator 4 (A1R/neurabin/RGS4) complex that dictates A1R signaling strength and response outcome in the brain. We have developed a peptide that blocks the A1R-neurabin interaction to enhance A1R activity. Intracerebroventricular or in administration of this peptide shows marked protection against kainate-induced seizures and neuronal death.
Furthermore, in an AD mouse model with spontaneous seizures, nasal delivery of this blocking peptide reduces epileptic spike frequency. Significantly, the anticonvulsant and neuroprotective effects of this peptide are achieved through enhanced A1R function in response to endogenous adenosine in the brain, thereby avoiding side effects associated with A1R activation in peripheral tissues and organs.
Our study reports on a potentially novel anticonvulsant therapy applicable to epilepsy and other neurological diseases with comorbid seizures.
#Peptide #delivered #nasal #spray #reduce #seizure #activity #protect #neurons #Alzheimers #epilepsy #Neuroscience #News