Peptide given by nasal spray may reduce seizure activity and protect neurons in Alzheimer’s and epilepsy

Summary: A1R-CT, a new peptide that binds to neurobin, can be given by nasal spray and has the potential to interrupt uncontrolled brain activity associated with TBI, stroke, epilepsy and Alzheimer’s.

A source: Medical College of Georgia at Augusta University

A new peptide boosts the brain’s natural mechanism to help prevent seizures and protect neurons in Alzheimer’s and epilepsy research models.

The A1R-CT peptide, administered via a nasal spray, shows promise in suppressing the uncontrolled electrical activity that is common after brain trauma, stroke and affects more than half of people with Alzheimer’s, researchers say. . Qin Wang, neuropharmacologist and founder of the Alzheimer’s Therapy Discovery Program at Augusta University Medical College of Georgia.

The fact that it can be delivered through the nose shows the peptide’s potential as a new rescue anti-seizure drug, for example helping to interrupt cluster seizures. Journal of research JCI Insight.

A1R-CT works by inhibiting neurabin, a protein that helps keep neurons from becoming hyperexcitable, disrupting normal connectivity and causing seizures, so they don’t overwork, he says.

The peptide is named after the protective adenosine 1 receptor on the surface of neurons, which is activated by adenosine, a chemical usually made in the brain by glial cells that support neurons in response to hyperexcitability.

“It’s a powerful receptor for silencing neurons,” Wang says. This natural, calming approach is also known to block electrical activity that can lead to heart palpitations. In fact, an injectable form of adenosine is used to treat heart palpitations.

“But the A1 receptor itself needs to be regulated, because if it’s activated too much, you fall asleep,” Wang says. “Neurons try to make sure everything is under control, and in most of us it works well. We don’t sleep at our desks. We don’t have seizures,” he says. Caffeine blocks the A1 receptor.

Alzheimer’s often accompanies seizures because the brain’s characteristic accumulation of amy and tau proteins disrupts communication between neurons, causing increased oxidative stress and resulting inflammation, and neurons can become hyperexcitable in response to altered dynamics, he said.

“There are a lot of things that go wrong with Alzheimer’s,” he says. Seizures can precede and certainly contribute to cognitive decline in Alzheimer’s, Wang said.

In this type of hyperactive scenario, activation of the A1 receptor by adenosine makes it a logical treatment target for seizures. But its widespread distribution throughout the body, including the heart, lungs, and kidneys, can cause widespread side effects.

Addressing neurons’ desire for homeostasis, Wang and his colleagues found that a protein called neurabin, which appears to be present primarily in the brain, maintains this balance by preventing A1 receptor hyperactivity.

The fact that neurabin is primarily found in the brain means that changing its activity should not have the same potential effects on the body as directly changing the activity of the A1 receptor, Wang said.

“Because neurobin is a brake, it doesn’t do too much,” Wang says. “But now we have to remove it to unlock the power of the A1.”

So they set out to develop a peptide that would block the interaction between the A1 receptor and neurobin, thus providing more of the natural protective, seizure-reducing benefit.

A1 receptor activation reduces the excitability of neurons by modulating ion channels – proteins in the cell membrane that allow other proteins to pass through the cell, which help generate electrical signals.

The result is called hyperpolarization, which means that the neuron is less likely to fire an electrical signal.

“The more polarized neurons are, the harder it is to excite them,” Wang says.

A1 receptor activation also reduces the release of the neurotransmitter glutamate produced by excitatory neurons. It also provides additional benefits to neurons, protecting them from insufficient oxygen and blood supply that can occur during injury. Scientists have noted a dramatic reduction in neuronal death in an Alzheimer’s model, for example, using their peptides.

Now they have shown that by reducing neurobin directly or with peptides, it enhances the action of A1C to reduce excess electrical activity in the brain. They showed that the peptide was also effective in a mouse model of Alzheimer’s mouse model of severe seizures. It works when injected directly into the brain or through a nasal spray.

To fully explore the peptide’s potential clinical benefits, the researchers considered nasal spray administration. They found a similar robust response in seizure and Alzheimer’s models.

Looking further at the effects of targeting neurabin, they found that neurabin-deficient mice had significantly shorter, less severe seizures and survived. Those with intact levels of neurabin were held for up to 30 minutes, and about 10% of the mice died soon after.

A1R-CT works by inhibiting neurabin, a protein that helps keep neurons from becoming hyperexcitable, disrupting normal connectivity and causing seizures, so they don’t overwork, he says. Image is in the public domain

Blocking the A1 receptor resulted in severe seizures in neurobin-deficient mice, with a death rate of over 50%.

Next steps include further research into ideal dosages and delivery times for the specific conditions the peptide could be used to treat.

The research team is also continuing to modify the peptide to ensure it works optimally and is seeking the necessary funding to conduct clinical trials.

Wang, a Georgia Research Alliance Distinguished Scientist, came to MCG in April 2021 from the University of Alabama at Birmingham to begin research on A1 receptors and peptide development. He continues to collaborate extensively with colleagues at UAB on the research he co-authored the new paper with. The first author Dr. Shalini Saggu is currently a lecturer in the Department of Neuroscience and Regenerative Medicine at MCG.

Epileptic seizures are common after brain trauma; stroke, which is an injury to the brain; and with chronic neurodegenerative diseases, including Alzheimer’s.

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It shows a sleeping woman

Scientists write that 64% of the 50 million people with Alzheimer’s disease. Patients may experience generalized tonic-clonic seizures in which they fall, shake, and become unresponsive. It can also be shorter and include repetitive hand or leg movements, lip smacking, and chewing.

Seizures are uncontrolled in about 40% of people, indicating an urgent need for new therapies, the researchers write, and current therapies are less effective in people with Alzheimer’s disease. Uncontrolled seizures can cause brain damage and cognitive impairment.

Adenosine is also a building block of our DNA and a component of cell fuel ATP.

Funding: The study was supported by the National Institutes of Health.

Neuropharmacology research news about it

Author: Tony Baker
A source: Medical College of Georgia at Augusta University
The connection: Tony Baker is from the Medical College of Georgia at Augusta University
Photo: Image is in the public domain

Original research: Open access.
“ADORA1-Neurabin Interaction Inhibiting Peptide Is Anticonvulsant and Inhibits Epilepsy in Alzheimer’s Model” Qin Wang et al. JCI Insights


Abstract

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, necessitating the development of new therapeutic agents.

Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism of self-inhibition of seizures and protection of neurons from excitotoxicity. However, the A1R target for neurological diseases has been hampered by the side effects associated with its wide manifestation outside the nervous system.

Here, we aim to target the neuron-specific A1R/neurabin/regulator of G protein signaling 4 (A1R/neurabin/RGS4) complex, which determines the strength and response outcome of A1R signaling in the brain. We have developed a peptide that blocks the A1R-neurabin interaction to enhance A1R activity. Intracerebroventricular administration of this peptide shows significant protection against kainate-induced seizures and neuronal death.

Furthermore, in a mouse model of AD with spontaneous seizures, intranasal delivery of this inhibitory peptide reduced the frequency of seizures. Notably, the anticonvulsant and neuroprotective effects of this peptide are achieved through enhanced A1R function in response to endogenous adenosine in the brain, thus avoiding adverse effects associated with A1R activation in peripheral tissues and organs.

Our research may inform new antiepileptic therapies for epilepsy and other neurological disorders.

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