Nigel Calcutt

Personal Information
Title Professor
Expertise Neuropathy & Neurocognition
Institution University of California San Diego
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Data Summary
Grants/SubContracts 2
Progress Reports 2
Presentations 2
Publications 21
Protocols 2
Committees 2

Cathepsin S inhibition and diabetic neuropathy
Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffer from the disease. There is no FDA-approved therapy to prevent distal degenerative neuropathy neuropathy or reverse the neuropathy that is already present in many newly diagnosed diabetic patients and which gets progressively worse over time. There is therefore a need to evaluate novel therapeutic approaches in preclinical studies with the anticipation that demonstration of efficacy will prompt clinical trials. To this end, we have begun to investigate the potential role of diabetes-induced increased expression of the enzyme cathepsin S and the subsequent increase in active fractalkine on indices of neuropathy. Our preliminary data demonstrates that diabetic rodents show increased tissue expression of cathepsin S and increased fractalkine levels in the plasma. Blocking cathepsin S activity using a highly selective inhibitor acutely relieves behavioral indices of pain in rodent models of neuropathy induced by either paclitaxel or diabetes, making cathepsin S inhibitors a promising therapy for painful neuropathy. During these initial studies we also noted that repeated administration of a cathepsin S inhibitors over many days leads to amelioration of pain that persists well beyond the effective life of the drug and indeed for many weeks after drug withdrawal. This leads us to propose that cathepsin S inhibition not only acutely ameliorates pain but also has the capacity to be disease modifying. We therefore propose to perform a pilot study in which diabetic rodents are treated with a cathepsin S inhibitor and the onset and progression of behavioral, functional and structural indices of peripheral neuropathy is followed in order to determine whether the treatment can prevent and reverse indices of degenerative neuropathy. Our intent in performing this pilot study is to illustrate the therapeutic potential of cathepsin S inhibition with the goal of prompting the further preclinical, and ultimately clinical, development of cathepsin S inhibitors as a treatment for diabetic degenerative neuropathy.
Detecting diabetic neuropathy in rodents by imaging corneal nerves
Visualization of corneal nerves by confocal microscopy is currently being developed as a sensitive and completely non-invasive method of detecting neuropathy in diabetic patients that allows the repeated measurements necessary for longitudinal studies of drug efficacy. Corneal confocal microscopy (CCM) has been applied to live rodents and other species and our exploratory studies indicate that corneal nerves can also be visualized ex vivo. In the proposal we will establish optimal conditions for visualizing and quantifying corneal nerves in rats and mice in vivo and in eyes from rats ex vivo. Once these conditions are established, we will use CCM to detect neuropathy in eyes of control and diabetic mice provided from new models of diabetes developed by the AMDCC. We will also compare the structural neuropathy detected by CCM with the current methods of phenotyping neuropathy in tissues from these animals which are reduced axonal calibre in the sciatic nerve and loss of intraepidermal nerve fibers in the paw skin. The sensitivity of CCM to detect onset and progression of neuropathy in a longitudinal study of the eyes of mouse models of type 1 and type 2 diabetes will also be studied and compared with onset and progression of nerve conduction velocity slowing and paw thermal hypoalgesia. The purpose of these studies is to establish the viability of CCM as a sensitive means of detecting neuropathy in diabetic rodents so that it can be used to phenotype new models of diabetes being developed by the AMDCC and to allow assessment of the efficacy of new therapeutics in rodent models prior to clinical trials using the same end point and equipment.

Progress Reports

Annual Reports
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Year: 2017; Items: 1

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy.
Calcutt NA, Smith DR, Frizzi K, Sabbir MG, Chowdhury SK, Mixcoatl-Zecuatl T, Saleh A, Muttalib N, Van der Ploeg R, Ochoa J, Gopaul A, Tessler L, Wess J, Jolivalt CG, Fernyhough P
The Journal of clinical investigation, 2017 (127), 608 - 622

Year: 2016; Items: 1

Peripheral Neuropathy in Mouse Models of Diabetes.
Jolivalt CG, Frizzi KE, Guernsey L, Marquez A, Ochoa J, Rodriguez M, Calcutt NA
Current protocols in mouse biology, 2016 (6), 223 - 55

Year: 2015; Items: 2

Efficacy of a long-acting c-peptide analogue against peripheral neuropathy in streptozotocin-diabetic mice.
Jolivalt CG, Rodriguez M, Wahren J, Calcutt NA
Diabetes, obesity & metabolism, 2015
Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation.
Rocca CJ, Kreymerman A, Ur SN, Frizzi KE, Naphade S, Lau A, Tran T, Calcutt NA, Goldberg JL, Cherqui S
Investigative ophthalmology & visual science, 2015 (56), 7214 - 23

Year: 2014; Items: 3

Animal Models of Diabetes-Induced Neuropathic Pain.
Lee-Kubli CA, Mixcoatl-Zecuatl T, Jolivalt CG, Calcutt NA
Current topics in behavioral neurosciences, 2014 (20), 147 - 170
Ciliary Neurotrophic Factor Reverses Aberrant Mitochondrial Bioenergetics Through the JAK/STAT Pathway in Cultured Sensory Neurons Derived from Streptozotocin-Induced Diabetic Rodents.
Chowdhury SR, Saleh A, Akude E, Smith DR, Morrow D, Tessler L, Calcutt NA, Fernyhough P
Cellular and molecular neurobiology, 2014 (34), 643 - 649
Submitted Externally
Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab).
The Working Group of Neurodiab, Biessels GJ, Bril V, Calcutt NA, Cameron NE, Cotter MA, Dobrowsky R, Feldman EL, Fernyhough P, Jakobsen J, Malik RA, Mizisin AP, Oates PJ, Obrosova IG, Pop-Busui R, Russell JW, Sima AA, Stevens MJ, Schmidt RE, Tesfaye S, Veves A, Vinik AI, Wright DE, Yagihashi S, Yorek MA, Ziegler D, Zochodne DW
Journal of the peripheral nervous system : JPNS, 2014 (19), 77 - 87

Year: 2013; Items: 4

Ciliary neurotrophic factor activates NF-?B to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents.
Saleh A, Roy Chowdhury SK, Smith DR, Balakrishnan S, Tessler L, Martens C, Morrow D, Schartner E, Frizzi KE, Calcutt NA, Fernyhough P
Neuropharmacology, 2013 (65), 65 - 73
Guaifenesin derivatives promote neurite outgrowth and protect diabetic mice from neuropathy.
Hadimani MB, Purohit MK, Vanampally C, Van der Ploeg R, Arballo V, Morrow D, Frizzi KE, Calcutt NA, Fernyhough P, Kotra LP
Journal of medicinal chemistry, 2013 (56), 5071 - 5078
Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type-1 diabetic rodents and the effects of topical insulin.
Chen DK, Frizzi KE, Guernsey LS, Ladt K, Mizisin AP, Calcutt NA
Journal of the peripheral nervous system : JPNS, 2013 (18), 306 - 315

Year: 2012; Items: 4

Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer's disease.
Jolivalt CG, Calcutt NA, Masliah E
Neuroscience, 2012 (202), 405 - 412
Expansion of neurofilament medium C terminus increases axonal diameter independent of increases in conduction velocity or myelin thickness.
Barry DM, Stevenson W, Bober BG, Wiese PJ, Dale JM, Barry GS, Byers NS, Strope JD, Chang R, Schulz DJ, Shah S, Calcutt NA, Gebremichael Y, Garcia ML
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012 (32), 6209 - 6219
Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.
Roy Chowdhury SK, Smith DR, Saleh A, Schapansky J, Marquez A, Gomes S, Akude E, Morrow D, Calcutt NA, Fernyhough P
Brain : a journal of neurology, 2012 (135), 1751 - 1766
Hypertension-induced peripheral neuropathy and the combined effects of hypertension and diabetes on nerve structure and function in rats.
Gregory JA, Jolivalt CG, Goor J, Mizisin AP, Calcutt NA
Acta Neuropathologica, 2012 (124), 561 - 573

Year: 2011; Items: 3

Muscle pathology without severe nerve pathology in a new mouse model of Charcot-Marie-Tooth disease type 2E.
Shen H, Barry DM, Dale JM, Garcia VB, Calcutt NA, Garcia ML
Human molecular genetics, 2011 (20), 2535 - 2548
GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice.
Jolivalt CG, Fineman M, Deacon CF, Carr RD, Calcutt NA
Diabetes, obesity & metabolism, 2011 (13), 990 - 1000
Considerations for quantification of lipids in nerve tissue using matrix-assisted laser desorption/ionization mass spectrometric imaging.
Landgraf RR, Garrett TJ, Conaway MC, Calcutt NA, Stacpoole PW, Yost RA
Rapid communications in mass spectrometry : RCM, 2011 (25), 3178 - 3184

Year: 2010; Items: 2

Diet-induced obesity in Sprague-Dawley rats causes microvascular and neural dysfunction.
Davidson EP, Coppey LJ, Calcutt NA, Oltman CL, Yorek MA
Diabetes/metabolism research and reviews, 2010 (26), 306 - 318

Year: 2009; Items: 1

Functional magnetic resonance imaging of the spinal cord during sensory stimulation in diabetic rats.
Malisza KL, Jones C, Gruwel ML, Foreman D, Fernyhough P, Calcutt NA
Journal of magnetic resonance imaging : JMRI, 2009 (30), 271 - 276
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Title YearTypeOptions
C) T1D Preclinical Testing Program (Nigel Calcutt)
Calcutt, Nigel (2009 P&F)
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