Biology subjects

Ricciardi, F.

Publications and source records attributed to Ricciardi, F..

3 recordsLinked to original sources

bioRxiv2024

A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of BLA input, and decreased feedforward inhibition of amygdala output neurons by BLA. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

neuroscience↗

bioRxiv2021

VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

Chemotherapy-induced neuropathic pain is a clinically relevant adverse effect of several anticancer drugs leading to dose reduction or therapy discontinuation. The lack of knowledge about the mechanisms of neuropathy development and pain chronicization makes chemotherapy-induced neuropathic pain treatment an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a neurotoxicity biomarker in a model of chemotherapy-induced neuropathy, and its decrease has been related to pain relief. Aim of this study was to clarify the VEGF-A-dependent pain signaling in the CNS for individuating new targeted therapeutic approaches. In mice, the intrathecal infusion of VEGF-A induced a dose-dependent noxious hypersensitivity mediated by the VEGF receptor 1 (VEGFR-1) as demonstrated by pharmacological and genetic tools. In electrophysiological study, VEGF-A stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord, VEGF-A increased in astrocytes of animals affected by neuropathy suggesting this cell population as a source of the potent pain mediator. Accordingly, the selective knockdown of astrocytic VEGF-A, by shRNAmir, blocked the development of oxaliplatin-induced neuropathic pain. Besides, the anti-VEGFR-1 mAb D16F7 (previously described as anticancer) effectively relieved neuropathic pain induced by chemotherapeutic agents. In conclusion, astrocyte-released VEGF-A is a new player in the complex neuron-glia network that oversees physiological and pathological pain and D16F7 mAb rises as a potent pain killer strategy.

neuroscience↗

bioRxiv2019

General Practitioners’ adherence to prescribing guidelines for statins in the United Kingdoms

ObjectiveIn this retrospective cohort study we aimed to assess, in 202,247 people who started a statin therapy between 2007-2014, the factors that led to the initiation of the drug. To do this we explored CVD risk factors singularly and in combinations as recorded in electronic health records in the year before they receive their first prescription and we compared the risk scores with that suggested by the NICE guideline at that time.\n\nMethodsWe summarised demographic characteristics and proportions of people with a risk score below the threshold. Regression-based analyses are performed to evaluate the association between the missingness of the risk score and relevant risk score components.\n\nResults45,364 individuals (22.4%) were prescribed statins without a record of a risk score being available in the year prior to the prescription date. When the risk score was available, 68,174 out of 156,883 patients were prescribed statins even with a score below the 20% threshold. Smoking status was the most frequently recorded variable (74.9% of the instances), followed by systolic blood pressure (71.6%) and total cholesterol (70%), while HDL cholesterol was the least recorded (34.1%). Cholesterol levels are positively associated with the missingness of the risk score, while systolic blood pressure shows a negative association.\n\nConclusionsGPs often start statins on people with no risk score recorded in their clinical records or in those with risk scores below the recommended threshold. Higher cholesterol values may result in a GP starting statin therapy without recording the other relevant components required to calculate a risk score.\n\nSTRENGTHS AND LIMITATIONS OF THIS STUDYO_LIOur cohort contains a large number of individuals: the study provide a representative picture of initiation of statins in UK primary care.\nC_LIO_LIWe specifically focus on which variables and factors GPs record in electronic databases in the year prior statin treatment initiation: this is the first study to directly tackle the issue of statins prescribing in the absence of all the information required by the NICE guideline\nC_LIO_LIWe are not able to verify if GPs actually used the records of the individual health indicators, when these were available, to calculate the risk score.\nC_LI

epidemiology↗