Biology subjects

Hardowar, L.

Publications and source records attributed to Hardowar, L..

3 recordsLinked to original sources

bioRxiv2023

Neuroinflammation induces nerve growth factor dependent nociceptor sensitisation in a neonatal rodent model of platinum-based chemotherapy induced neuropathic pain

Chemotherapy-induced neuropathic pain (CINP) is a common adverse health related comorbidity that manifests later in life in paediatric patients treated for cancer. CIPN pathology progressively develops over time resulting in a delayed but long-lasting neuropathic pain. Current analgesic strategies are ineffective, aligning closely with our lack of understanding of CINP. Recent studies have indicated alterations in sensory neuronal maturation as component of CINP. The aim of this study was to investigate how cisplatin induces nerve growth factor mediated neuroinflammation and nociceptor sensitisation. In a rodent model of cisplatin induced survivorship pain, there was a significant infiltration of nerve growth factor positive macrophages into the dorsal root ganglia (DRG), demonstrating a robust neuroinflammatory response. Additionally, it was observed that CD11b/F480 positive monocyte/macrophages challenged with cisplatin expressed more NGF. Additionally, DRG derived primary sensory neuron cultures from neonatal mice demonstrated enhanced NGF-dependent TRPV1 mediated nociceptor activity after cisplatin treatment. Increased nociceptor activity was also observed when cultured neurons were treated with conditioned media from cisplatin activated monocyte/macrophages. This elevated nociceptor activity was dose-dependently inhibited by a neutralising monoclonal antibody to NGF. Intraperitoneal administration of NGF neutralising antibody significant reduction in mechanical hypersensitivity was given to mice with cisplatin-induced juvenile survivorship pain there was a as well as suppression of cisplatin induced aberrant nociceptor intraepidermal nerve fibre density. These findings identify the NGF/TrkA signalling pathway as a potential novel therapeutic target for analgesia in adult survivors of childhood cancer.

neuroscience↗

bioRxiv2023

Spatial proteomics reveals heterogeneity in neural markers underpinning high-fat diet-induced myopathy in male mice.

Metabolic dysfunction in skeletal muscle disturbs its contractile response as well as its innervation and vascular networks. The molecular drivers responsible for affecting decline in function remain poorly defined. To provide insight and locate these, we mapped changes in the spatial proteome occurring as a result of impaired metabolic health. We exposed male mice (C57/BL6J) to diet induced obesity to investigate the impairment of muscle metabolic function and myopathy. We conducted digital spatial profiling using the NanoString GeoMx(R) platform on recovered skeletal muscle (tibialis anterior) comparing it to standard fed controls. Digital spatial profiling revealed areas with shifts in the contractile protein desmin and CD31 expression, a marker of tissue stress and cellular maladaptation. We find increased expression of proinflammatory markers were identified in areas of elevated Desmin in obese samples compared to controls. Our data suggest a dietary-driven relationship between the spatial abundance of the sarcomere protein desmin and the influx of neural and inflammatory mediators to muscle. This supports the concept of pro-inflammatory events underpinning the muscle metabolic dysfunction associated with chronic non-communicative diseases such as type 2 diabetes, metabolic syndrome, and chronic obstructive pulmonary disorder.

physiology↗

bioRxiv2021

Hypoxia induced carbonic anhydrase mediated dorsal horn sensory neuron activation and induction ofneuropathic pain

Neuropathic pain such as that seen in diabetes mellitus, results in part from central sensitisation in the spinal cord dorsal horn. However, the mechanisms responsible for such sensitisation remain unclear. There is evidence that disturbances in the integrity of the spinal vascular network can be a causative factor in the development of neuropathic pain. Here we show that reduced blood flow and vascularity of the dorsal horn leads to the onset of neuropathic pain. Using rodent models (type 1 diabetes and an inducible endothelial specific vascular endothelial growth factor receptor 2 knockout mouse) that result in degeneration of the endothelium in the dorsal horn we show that spinal cord vasculopathy results in nociceptive behavioural hypersensitivity. This also results in increased hypoxia in dorsal horn sensory neurons, depicted by increased expression of hypoxia markers hypoxia inducible factor 1, glucose transporter 3 and carbonic anhydrase 7. Furthermore, inducing hypoxia via intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn sensory neurons as well as mechanical and thermal hypersensitivity. This shows that hypoxic signalling induced by reduced vascularity results in increased hypersensitivity and pain. Inhibition of carbonic anhydrase activity, through intraperitoneal injection of acetazolamide, inhibited hypoxia induced pain behaviours. This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which sensory neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain.

neuroscience↗