Silvia Benemei

The concept of neurogenic inflammation.

Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic inflammation encompasses a series of vascular and non‐vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene‐related peptide. The reduction of neurogenic inflammatory responses may be key in the mode of action of the adrenergic α1‐adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the α1‐adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c‐fos– a marker of nociceptive pathway activation – evoked by cyclophosphamide in rats.

TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism

Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1.

CGRP receptors in the control of pain and inflammation.

Calcitonin gene related peptide (CGRP) has been proposed to contribute to pain transmission and inflammation and for these reasons to the mechanism of migraine. CGRP is, in fact, expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion. Release of CGRP in the dorsal spinal cord has been associated to nociceptive transmission, and release from perivascular nerve endings causes neurogenic vasodilatation. CGRP levels increase in the cranial circulation during migraine attacks, and GRP injection in migraineurs results in migraine-like attacks. Most importantly, two chemically unrelated CGRP-receptor antagonists, the parenteral agent, olcegepant, and the orally available telcagepant demonstrated efficacy in the treatment of migraine attacks, thus supporting CGRP as an important mediator in migraine.

Treatment With β-Blockers and Reduced Disease Progression in Patients With Thick Melanoma

Preclinical evidence shows that β-adrenoceptor antagonists (β-blockers) inhibit tumor and metastasis progression in animal models of melanoma. We hypothesized that the use of β-blockers for concomitant diseases is associated with a reduced risk of progression of thick (Breslow thickness >1 mm) malignant melanoma. Two patient subgroups were identified from the medical records of 121 consecutive patients with a thick melanoma. Of these, 30 patients had been prescribed β-blockers for 1 year or more (treated subgroup), whereas the other 91 were untreated. After a median follow-up time of 2.5 years, tumor progression was observed in 3.3% of the treated subgroup and in 34.1% of the untreated subgroup. The Cox model on progression indicated a 36% (95% confidence interval, 11%-54%) (P = .002) risk reduction for each year of β-blocker use. No deaths were observed in the treated group, whereas in the untreated group 24 patients died. To our knowledge, the present study suggests for the first time that exposure to β-blockers for 1 year or more is associated with a reduced risk of progression of thick malignant melanoma, indicating the need for larger epidemiological studies and randomized clinical trials.

Ethanol Causes Neurogenic Vasodilation by TRPV1 Activation and CGRP Release in the Trigeminovascular System of The Guinea Pig

Ethanol stimulating transient receptor potential vanilloid 1 (TRPV1) on primary sensory neurons promotes neurogenic inflammation, including calcitonin gene-related peptide (CGRP)-mediated coronary dilation. Alcoholic beverages trigger migraine attacks and activation of trigeminal neurons plays a role in migraine. We have investigated in guinea pigs whether ethanol by TRPV1 stimulation causes neurogenic inflammation in the trigeminovascular system. Ethanolevoked release of neuropeptides from slices of dura mater was abolished by Ca2+ removal, capsaicin pretreatment and the TRPV1 antagonist, capsazepine. Intragastric ethanol increased plasma extravasation in dura mater, an effect abolished by capsazepine and the NK1 receptor antagonist, SR140333, and caused vasodilation around the middle meningeal artery, an effect abolished by capsazepine and the CGRP receptor antagonist, BIBN4096BS. Vasodilation of meningeal vessels by TRPV1 activation and CGRP release may be relevant to the mechanism by which alcohol ingestion triggers migraine attacks.

Adherence to Statin Treatment and Health Outcomes in an Italian Cohort of Newly Treated Patients: Results From an Administrative Database Analysis

BACKGROUND Adherence to statin treatment is expected to be associated with health outcomes. Much of the available evidence is derived from studies conducted on selected populations (eg, Medicaid population), on specific cohorts of patients (eg, patients with diabetes mellitus or those who have experienced acute myocardial infarction [AMI]), or with respect to a single outcome (eg, only death or only AMI). OBJECTIVE The aim of this study was to evaluate the association between adherence to statin therapy and all-cause mortality and cardiovascular morbidity (AMI and stroke) in an unselected cohort of newly treated patients. METHODS We performed a population-based retrospective cohort study that included adult patients with a first prescription of a statin from January 1, 2004, through December 31, 2006, using data from the administrative databases of the Local Health Unit of Florence in Italy. Adherence to statin treatment was estimated as the proportion of days covered (PDC) by filled prescriptions and classified as low (PDC, 21%-40%), intermediate-low (PDC, 41%-60%), intermediate-high (PDC, 61%-80%), and high (PDC, >80%). Cases with PDC ≤20% were excluded. A Cox regression model was used to investigate the association between adherence to treatment and all-cause mortality and hospitalization for AMI or stroke. RESULTS The cohort consisted of 19,232 patients (9823 men and 9409 women) aged 18 to 102 years (mean [SD], 66.5 [11.4] years): 20.1% had been previously hospitalized for cardiovascular events and 17.6% had been treated with hypoglycemic drugs. Adherence to statins was low in 4427 patients (23.0%), intermediate-low in 3117 (16.2%), intermediate-high in 3784 (19.7%), and high in 7904 (41.1%). Lower-adherent patients were younger and had fewer comorbidities compared with higher-adherent patients. In our multivariable analyses, high adherence was significantly associated with decreased risk of all-cause death, AMI, or stroke. Compared with low adherence (hazard ratio [HR] = 1), the risk was lower in intermediate-low adherence (HR = 0.83; 95% confidence interval [CI], 0.71-0.98; P < 0.05) and much lower in intermediate-high (HR = 0.60; 95% CI, 0.51-0.70; P < 0.001) and high adherence (HR = 0.61; 95% CI, 0.54-0.71; P < 0.001). CONCLUSIONS In this Italian cohort of newly treated patients, suboptimal adherence to statins occurred in a substantial proportion of patients and was associated with increased risk of adverse health outcomes.

Adherence to antihypertensive medications and health outcomes among newly treated hypertensive patients

Objective: To evaluate adherence to antihypertensive therapy (AHT) and the association between adherence to AHT, all-cause mortality, and cardiovascular (CV) morbidity in a large cohort of patients newly treated with antihypertensives in a clinical practice setting. Methods: An administrative database kept by the Local Health Unit of Florence (Italy) listing patient baseline characteristics, drug prescription, and hospital admission information was used to perform a population-based retrospective study including patients newly treated with antihypertensives, ≥18 years of age, with a first prescription between January 1, 2004 and December 31, 2006. Patients using antihypertensives for secondary prevention of CV disease, occasional spot users, and patients with early CV events, were excluded from the study cohort. Adherence to AHT was calculated and classified as poor, moderate, good, and excellent. A Cox regression model was conducted to determine the association among adherence to AHT and risk of all-cause mortality, stroke, or acute myocardial infarction. Results: A total of 31,306 patients, 15,031 men (48.0%), and 16,275 women (52.0%), with a mean age of 60.2 ± 14.5 years was included in the study. Adherence to AHT was poor in 8038 patients (25.7% of included patients), moderate in 4640 (14.8%), good in 5651 (18.1%), and excellent in 12,977 (41.5%). Compared with patients with poor adherence (hazard ratio [HR] = 1), the risk of all-cause death, stroke, or acute myocardial infarction was significantly lower in patients with good (HR = 0.69, P < 0.001) and excellent adherence (HR = 0.53, P < 0.001). Conclusions: These findings indicate that suboptimal adherence to AHT occurs in a substantial proportion of patients and is associated with poor health outcomes already in primary prevention of CV diseases. For health authorities, this preliminary evidence underlines the need for monitoring and improving medication adherence in clinical practice.

The TRPA1 channel in migraine mechanism and treatment

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain‐provoking exogenous and endogenous agents, which release the pro‐migraine peptide, calcitonin gene‐related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

The TRPA1 Channel in Inflammatory and Neuropathic Pain and Migraine

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, is primarily localized to a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of nociceptors produces and releases the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammatory responses. TRPA1 is activated by a number of exogenous compounds, including molecules of botanical origin, environmental irritants, and medicines. However, the most prominent feature of TRPA1 resides in its unique sensitivity for large series of reactive byproducts of oxidative and nitrative stress. Here, the role of TRPA1 in models of different types of pain, including inflammatory and neuropathic pain and migraine, is summarized. Specific attention is paid to TRPA1 as the main contributing mechanism to the transition of mechanical and cold hypersensitivity from an acute to a chronic condition and as the primary transducing pathway by which oxidative/nitrative stress produces acute nociception, allodynia, and hyperalgesia. A series of migraine triggers or medicines have been reported to modulate TRPA1 activity and the ensuing CGRP release. Thus, TRPA1 antagonists may be beneficial in the treatment of inflammatory and neuropathic pain and migraine.

Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel.

Summary Parthenolide, a major constituent of feverfew, acts as a partial agonist of TRPA1. Parthenolide’s ability to target TRPA1 could explain its therapeutic effects on migraine. Abstract Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene‐related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew’s antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1‐expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP‐mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.