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Sarm1 Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice.

ABSTRACT: Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes, but any treatment toward the development of DPN is not yet available. Axon degeneration is an early feature of many peripheral neuropathies, including DPN. Delay of axon degeneration has beneficial effects on various neurodegenerative diseases, but its effect on DPN is yet to be elucidated. Deficiency of Sarm1 significantly attenuates axon degeneration in several models, but the effect of Sarm1 deficiency on DPN is still unclear. In this study, we show that Sarm1 knockout mice exhibit normal glucose metabolism and pain sensitivity, and deletion of the Sarm1 gene alleviates hypoalgesia in streptozotocin-induced diabetic mice. Moreover, Sarm1 gene deficiency attenuates intraepidermal nerve fiber loss in footpad skin; alleviates axon degeneration, the change of g-ratio in sciatic nerves, and NAD+ decrease; and relieves axonal outgrowth retardation of dorsal root ganglia from diabetic mice. In addition, Sarm1 gene deficiency markedly diminishes the changes of gene expression profile induced by streptozotocin in the sciatic nerve, especially some abundant genes involved in neurodegenerative diseases. These findings demonstrate that Sarm1 gene deficiency attenuates DPN in mice and suggest that slowing down axon degeneration is a potential promising strategy to combat DPN.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC6804630 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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<i>Sarm1</i> Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice.

Cheng Yalan Y Liu Jun J Luan Yi Y Liu Zhiyuan Z Lai Hejin H Zhong Wuling W Yang Yale Y Yu Huimin H Feng Ning N Wang Hui H Huang Rui R He Zhishui Z Yan Menghong M Zhang Fang F Sun Yan-Gang YG Ying Hao H Guo Feifan F Zhai Qiwei Q

Diabetes 20190822 11

Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes, but any treatment toward the development of DPN is not yet available. Axon degeneration is an early feature of many peripheral neuropathies, including DPN. Delay of axon degeneration has beneficial effects on various neurodegenerative diseases, but its effect on DPN is yet to be elucidated. Deficiency of <i>Sarm1</i> significantly attenuates axon degeneration in several models, but the effect ...[more]

PMID: 31439642

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Project description:Peripheral polyneuropathy is a common and dose-limiting side effect of many important chemotherapeutic agents. Most such neuropathies are characterized by early axonal degeneration, yet therapies that inhibit this axonal destruction process do not currently exist. Recently, we and others discovered that genetic deletion of SARM1 (sterile alpha and TIR motif containing protein 1) dramatically protects axons from degeneration after axotomy in mice. This finding fuels hope that inhibition of SARM1 or its downstream components can be used therapeutically in patients threatened by axonal loss. However, axon loss in most neuropathies, including chemotherapy-induced peripheral neuropathy, is the result of subacute/chronic processes that may be regulated differently than the acute, one time insult of axotomy. Here we evaluate if genetic deletion of SARM1 decreases axonal degeneration in a mouse model of neuropathy induced by the chemotherapeutic agent vincristine. In wild-type mice, 4 weeks of twice-weekly intraperitoneal injections of 1.5 mg/kg vincristine cause pronounced mechanical and heat hyperalgesia, a significant decrease in tail compound nerve action potential amplitude, loss of intraepidermal nerve fibres and significant degeneration of myelinated axons in both the distal sural nerve and nerves of the toe. Neither the proximal sural nerve nor the motor tibial nerve exhibit axon loss. These findings are consistent with the development of a distal, sensory predominant axonal polyneuropathy that mimics vincristine-induced peripheral polyneuropathy in humans. Using the same regimen of vincristine treatment in SARM1 knockout mice, the development of mechanical and heat hyperalgesia is blocked and the loss in tail compound nerve action potential amplitude is prevented. Moreover, SARM1 knockout mice do not lose unmyelinated fibres in the skin or myelinated axons in the sural nerve and toe after vincristine. Hence, genetic deletion of SARM1 blocks the development of vincristine-induced peripheral polyneuropathy in mice. Our results reveal that subacute/chronic axon loss induced by vincristine occurs via a SARM1 mediated axonal destruction pathway, and that blocking this pathway prevents the development of vincristine-induced peripheral polyneuropathy. These findings, in conjunction with previous studies with axotomy and traumatic brain injury, establish SARM1 as the central determinant of a fundamental axonal degeneration pathway that is activated by diverse insults. We suggest that targeting SARM1 or its downstream effectors may be a viable therapeutic option to prevent vincristine-induced peripheral polyneuropathy and possibly other peripheral polyneuropathies.

Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus and can lead to serious complications. Therapeutic strategies for pain control are available but there are few approaches that influence neurological deficits such as numbness.AimTo investigate the effectiveness of acupuncture on improving neurological deficits in patients suffering from type 2 DPN.MethodsThe acupuncture in DPN (ACUDPN) study was a two-armed, randomized, controlled, parallel group, open, multicenter clinical trial. Patients were randomized in a 1:1 ratio into two groups: The acupuncture group received 12 acupuncture treatments over 8 wk, and the control group was on a waiting list during the first 16 wk, before it received the same treatment as the other group. Both groups received routine care. Outcome parameters were evaluated after 8, 16 and 24 wk and included neurological scores, such as an 11-point numeric rating scale (NRS) 11 for hypesthesia, neuropathic pain symptom inventory (NPSI), neuropathy deficit score (NDS), neuropathy symptom score (NSS); nerve conduction studies (NCS) were assessed with a handheld point-of-care device.ResultsSixty-two participants were included. The NRS for numbness showed a difference of 2.3 (P < 0.001) in favor of the acupuncture group, the effect persisted until week 16 with a difference of 2.2 (P < 0.001) between groups and 1.8 points at week 24 compared to baseline. The NPSI was improved in the acupuncture group by 12.6 points (P < 0.001) at week 8, the NSS score at week 8 with a difference of 1.3 (P < 0.001); the NDS and the TNSc score improved for the acupuncture group in week 8, with a difference of 2.0 points (P < 0.001) compared to the control group. Effects were persistent in week 16 with a difference of 1.8 points (P < 0.05). The NCS showed no meaningful changes. In both groups only minor side effects were reported.ConclusionStudy results suggest that acupuncture may be beneficial in type 2 diabetic DPN and seems to lead to a reduction in neurological deficits. No serious adverse events were recorded and the adherence to treatment was high. Confirmatory randomized sham-controlled clinical studies with adequate patient numbers are needed to confirm the results.

Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes severely afflicting the patients, while there is yet no effective medication against this disease. As Kv2.1 channel functions potently in regulating neurological disorders, the present work was to investigate the regulation of Kv2.1 channel against DPN-like pathology of DPN model mice by using selective Kv2.1 inhibitor SP6616 (ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate) as a probe.MethodsSTZ-induced type 1 diabetic mice with DPN (STZ mice) were defined at 12 weeks of age (4 weeks after STZ injection) through behavioral tests, and db/db (BKS Cg-m+/+Leprdb/J) type 2 diabetic mice with DPN (db/db mice) were at 18 weeks of age. SP6616 was administered daily via intraperitoneal injection for 4 weeks. The mechanisms underlying the amelioration of SP6616 on DPN-like pathology were investigated by RT-PCR, western blot and immunohistochemistry technical approaches against diabetic mice, and verified against the STZ mice with Kv2.1 knockdown in dorsal root ganglion (DRG) tissue by injection of adeno associated virus AAV9-Kv2.1-RNAi. Amelioration of SP6616 on the pathological behaviors of diabetic mice was assessed against tactile allodynia, thermal sensitivity and motor nerve conduction velocity (MNCV).FindingsSP6616 treatment effectively ameliorated the threshold of mechanical stimuli, thermal sensitivity and MNCV of diabetic mice. Mechanism research results indicated that SP6616 suppressed Kv2.1 expression, increased the number of intraepidermal nerve fibers (IENFs), improved peripheral nerve structure and vascular function in DRG tissue. In addition, SP6616 improved mitochondrial dysfunction through Kv2.1/CaMKKβ/AMPK/PGC-1α pathway, repressed inflammatory response by inhibiting Kv2.1/NF-κB signaling and alleviated apoptosis of DRG neuron through Kv2.1-mediated regulation of Bcl-2 family proteins and Caspase-3 in diabetic mice.InterpretationOur work has highly supported the beneficial of Kv2.1 inhibition in ameliorating DPN-like pathology and highlighted the potential of SP6616 in the treatment of DPN.FundingPlease see funding sources.

Project description:Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.

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Sarm1 Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice.

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<i>Sarm1</i> Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice.

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