HoldsUp

Paul Fernyhough

Paul Fernyhough is a researcher in the field of neuroscience with a focus on peripheral nerve disorders. His published research investigates mechanisms and treatments for diabetic peripheral neuropathy, mitochondrial dysfunction, and neuritogenesis. In particular, his work explores the therapeutic potential of muscarinic acetylcholine receptor antagonists to stimulate axonal repair and neurite outgrowth in sensory neurons.

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What they said on air - citing their own research

3 citing their own research

0:00:00supportedvery lowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Targeting mitochondria to increase their function can overcome the neurodegenerative process in peripheral neuropathy.

"if you target the mitochondria to drive up its function, you can overcome the degenerative process." (said at 0:00:00)

Preclinical models of peripheral neuropathy (such as diabetic, chemotherapy-induced, and HIV-associated neuropathies) demonstrate that enhancing mitochondrial bioenergetics and calcium homeostasis (e.g., via muscarinic receptor antagonism or TRPM3 activation) can promote axonal repair and overcome neurodegenerative phenotypes. However, while these strategies show promising disease-modifying potential in cellular and animal models, evidence in human clinical trials remains preliminary.

0:18:25supportedlowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Excess glucose entering neurons shifts their metabolism toward glycolysis, leading to downregulation and loss of mitochondria.

"Its metabolism is affected by all this sugar that's coming into the neuron. And as a result, it becomes more reliant upon glycolysis. And so, it actually switches off its mitochondria as almost as an inbuilt system. And what this means though in terms of neurons, especially the nerve endings, which have very high energy requirements, you actually see a loss of mitochondria, and it's been shown in human tissue as well as animal studies." (said at 0:18:25)

Nutrient excess and elevated intracellular glucose concentrations in sensory neurons trigger metabolic maladaptation via nutrient-sensing pathways (such as AMPK/SIRT/PGC-1α), causing suppression of mitochondrial oxidative phosphorylation and a shift toward glycolysis. This downregulation of mitochondrial respiratory chain gene expression, function, and distal energetic capacity in energy-demanding nerve endings has been demonstrated in both animal models of diabetes and human tissue biopsies.

0:34:05supportedvery lowtheir own paperExciting Developments in the Treatment of Peripheral Neuropa

Acetylcholine binding to the muscarinic receptor sends a negative signal that inhibits sensory neuron growth, and blocking this receptor with an antagonist removes this cholinergic constraint and increases nerve growth.

"what we've discovered is that the muscarinic receptor is a key component of a negative influence. So acetylcholine, which is a neurotransmitter, binds to the muscarinic receptor, sends a negative signal that inhibits growth. And we've done lots of studies to uncover all that. And so, when you come in with an antagonist or a blocker of the receptor, you block this cholinergic constraint, as we as we termed it, and you see increased growth." (said at 0:34:05)

Preclinical in vitro and animal studies demonstrate that endogenous acetylcholine acts via muscarinic acetylcholine type 1 receptors (M1R) to exert a tonic inhibitory effect ('cholinergic constraint') on adult sensory neuron neurite outgrowth and mitochondrial function. Genetic knockout of M1R or pharmacological blockade using selective M1R antagonists (such as pirenzepine or MT7) removes this inhibition and promotes sensory neuron growth and peripheral nerve regeneration.

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