Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research

Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Neurogenic Inflammation: One of the Participants of Migraine and the Contribution of Translational Research

Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Pre-emptive PPAR-γ Activation Abolishes Development of Nerve Injury-induced Behavioral Hypersensitivity: Elucidating Underlying Mechanisms

Background: Neuropathic pain is a chronic incapacitating painful condition for which there is no effective treatment. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play key roles in modulating immune and inflammatory responses. The antinociceptive properties of PPAR-γ activation on development of neuropathic pain are not fully known. Objective: To determine the role of PPAR-γ activation on the development of neuropathic pain following chronic constriction injury and to elucidate underlying mechanisms. Methodology: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pre-emptive administration of pioglitazone, a PPAR-γ agonist (3, 10 or 30 mg/kg, i.p. 1 hr before surgery and continued once daily for 2 weeks) dose-dependently attenuated paw withdrawal latency to cold (allodynia) and thermal (hyperalgesia) stimuli. Pioglitazone significantly reduced elevated TBARS, protein carbonylation, nitrite levels and markedly restored depleted GSH, and reduction in activities of SOD and catalase in injured nerves. Further, pioglitazone markedly reduced plasma extravasation and levels of pro-inflammatory cytokines TNF-α and IL-1β following nerve injury. Moreover, pioglitazone did not alter the locomotor activity. Pretreatment with PPAR-γ antagonist BADGE (30 mg/kg, i.p.) blocked the beneficial effects of pioglitazone. Essentially, pioglitazone promoted the long-lasing recovery and also prevented the development of neuropathic pain even after treatment termination. Conclusion: Pioglitazone, a PPAR-γ agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation. Our findings strongly suggest that pre-emptive activation of PPAR-γ prevented or at least delayed the development of nerve injury-induced pain hypersensitivity.

Selective Inhibition of the C-Domain of ACE (Angiotensin-Converting Enzyme) Combined With Inhibition of NEP (Neprilysin): A Potential New Therapy for Hypertension

Combined inhibition of NEP (neutral endopeptidase) and ACE (angiotensin-converting enzyme), without unwanted effects, remains an attractive therapeutic strategy in cardiovascular medicine. Omapatrilat, a dual NEP inhibitor–ACE inhibitor, was a promising antihypertensive drug but failed in trials due to angioedema, an effect possibly caused by inhibition of both the N- and C-domains of ACE. Here, we aimed to determine whether lisinopril-tryptophan (lisW-S), a C-domain specific ACE inhibitor that preserves the N-domain catalytic activity, together with sacubitril (NEP inhibitor), differentially influences cardiovascular function and vascular permeability in hypertension compared with omapatrilat and lisinopril+sacubitril which inhibits both the ACE C- and N-domains. Ang II (angiotensin II)–dependent hypertensive mice (transgenic mice expressing active human renin in the liver [also known as LinA3]) received vehicle, sacubitril, lisW-S, lisinopril, lisinopril+sacubitril, or lisW-S+sacubitril for 4 weeks. Systolic blood pressure was increased in LinA3 mice, along with cardiac hypertrophy/dysfunction, impaired endothelium-dependent vasorelaxation, hypercontractile responses, vascular remodeling, and renal inflammation. LisW-S+sacubitril, lisinopril+sacubitril, and omapatrilat reduced systolic blood pressure and normalized cardiovascular remodeling and vascular hypercontractile responses in LinA3 mice. Although lisinopril+sacubitril and omapatrilat improved Ach-induced vasorelaxation, lisW-S+sacubitril had no effect. Endothelial permeability (Evans Blue assessment) was increased in omapatrilat but not in LisW-S+sacubitril–treated mice. In conclusion, lisW-S combined with sacubitril reduced systolic blood pressure and improved cardiac dysfunction in LinA3 mice, similar to omapatrilat but without effects on endothelium-dependent vasorelaxation. Moreover, increased vascular leakage (plasma extravasation) induced by omapatrilat was not evident in mice treated with lisW-S+sacubitril. Targeting ACE C-domain and NEP as a combination therapy may be as effective as omapatrilat in lowering systolic blood pressure, but without inducing vascular permeability and endothelial injury.

Salivary complement inhibitors from mosquitoes: Structure and mechanism of action

Inhibition of the alternative pathway (AP) of complement by saliva from Anopheles mosquitoes facilitates feeding by blocking production of the anaphylatoxins C3a and C5a which activate mast cells leading to plasma extravasation, pain and itching. We have previously shown that albicin, a member of the SG7 protein family from An. albimanus blocks the AP by binding to and inhibiting the function of the C3 convertase, C3bBb. Here we show that SG7.AF, the albicin homolog from An. freeborni, has a similar potency to albicin but is more active in the presence of properdin, a plasma protein that acts to stabilize C3bBb. Conversely, albicin is highly active in the absence or presence of properdin. Albicin and SG7.AF stabilize the C3bBb complex in a form that accumulates on surface plasmon resonance (SPR) surfaces coated with properdin but SG7.AF binds with lower affinity than albicin. Albicin induces oligomerization of the complex in solution, suggesting that it is oligomerization that leads to stabilization on SPR surfaces. Anophensin, the albicin ortholog from An. stephensi, is only weakly active as an inhibitor of the AP, suggesting that the SG7 family may play a different functional role in this species and other species of the subgenus Cellia, containing the major malaria vectors in Africa and Asia. Crystal structures of albicin and SG7.AF reveal a novel four-helix bundle arrangement, that is stabilized by a N-terminal hydrogen bonding network. These structures provide insight into the SG7 family and related mosquito salivary proteins including the platelet-inhibitory 30kDa family.

Severe Decompression Sickness Associated with Shock and Acute Respiratory Failure

Decompression sickness (DCS) is a well-recognized complication of diving but rarely results in shock or respiratory failure. We report a case of severe DCS in a diver associated with shock and respiratory failure requiring mechanical ventilation. A healthy 50-year-old male diver dove to a depth of 218 feet for 43 minutes while breathing air but omitted 6.5 hours of air decompression due to diver error. The clinical presentation was remarkable for loss of consciousness, hypotension, cutis marmorata, peripheral edema, and severe hypoxia requiring mechanical ventilation with diffuse lung opacities on chest radiograph. Laboratories were significant for polycythemia and hypoalbuminemia. A single hyperbaric oxygen treatment was provided on the day of admission during which shock worsened requiring aggressive volume resuscitation and three vasopressors. In the first 37 hours of hospitalization, 22 liters of crystalloid and multiple albumin boluses were administered for refractory hypotension by which time all vasopressors had been discontinued and blood pressure had normalized. He required 10 days of mechanical ventilation and was discharged on day 21 with mild DCS-related neurologic deficits. This clinical course is characteristic of DCS-related shock wherein bubble-endothelial interactions cause a transient capillary leak syndrome associated with plasma extravasation, hemoconcentration, and hypovolemia. The pathophysiology and typical clinical course of DCS-related shock suggest the need for aggressive but time-limited administration of crystalloid and albumin. Because hyperbaric oxygen is the primary treatment for DCS, treatment with hyperbaric oxygen should be strongly considered even in the face of extreme critical illness.

Resiniferatoxin (RTX) ameliorates acute respiratory distress syndrome (ARDS) in a rodent model of lung injury

Acute lung injury (ALI) is associated with cytokine release, pulmonary edema and in the longer term, fibrosis. A severe cytokine storm and pulmonary pathology can cause respiratory failure due to acute respiratory distress syndrome (ARDS), which is one of the major causes of mortality associated with ALI. In this study, we aimed to determine a novel neural component through cardiopulmonary spinal afferents that mediates lung pathology during ALI/ARDS. We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Considering the translational potential of stellate ganglia delivery of RTX, we further examined the effects of stellate RTX on blood gas exchange and lung edema in the ALI rat model. Our data suggest that intra-stellate ganglia injection of RTX improved pO2 and blood acidosis 7 days post ALI. It also reduced wet lung weight in bleomycin treated rats, indicating a reduction in lung edema. Taken together, this study suggests that cardiopulmonary spinal afferents play a critical role in lung inflammation and edema post ALI. This study shows the translational potential for ganglionic administration of RTX in ARDS.

Analgesic and Anti-inflammatory Effects of Caryocar brasiliense

Background: Caryocar brasiliense, popularly known as pequi, is widely distributed in the Amazon rainforest and Brazilian savannah. The fruit obtained from pequi is used in cooking and has folk use as an anti-inflammatory and for the treatment of respiratory disease. Until now, these two properties had not been scientifically demonstrated for Pequi oil in a carrageenan model. Objective: Our group determined the composition and safe use of Pequi oil from the Savannah of Campo Grande, and the anti-inflammatory and anti-nociceptive activities of this pequi oil were investigated in vivo models. Materials and Methods: Doses of 300, 700, and 1000 mg/kg of Pequi oil were administered orally (p.o.) to Swiss male mice, and three parameters of inflammation (mechanical hyperalgesia, cold, hyperalgesia, and oedema) were analyzed in a carrageenan model to induce an inflammatory paw state. Results and Discussion: The effects of Pequi oil were also carrageenan in pleurisy model, formalin, and acetic acid induced nociception. Oral administration of 1,000 mg/kg orally Pequi oil (p.o.) inhibited (*P<0.05), the migration of total leukocytes, but not alter plasma extravasation, in the pleurisy model when compared to control groups. The paw edema was inhibited with doses of 700 (P <0.05) and 1,000 mg (P<0.001) of pequi oil after 1, 2, and 4 hours after carrageenan. Pequi oil (1,000 mg/kg) also blocked the mechanical hyperalgesy and reduced cold allodynia induced by carrageenan in paw (P <0.05). Pequi oil treatment (1,000 mg/kg) almost blocked (P < 0.001) all parameters of nociception observed in formalin and acid acetic test. Conclusion: This is the first time that the analgesic and anti-inflammatory effects of Pequi oil have been shown.

Capillary leak syndrome (CLS) from rituximab therapy of lymphoma

Capillary Leak Syndome (CLS) is characterized by plasma extravasation into the interstitium with resultant hypotension, anasarca, hemoconcentration, and hypoalbuminemia in the absence of albuminuria. Initially reported in Clarkson’s disease (systemic capillary leak syndrome, SCLS), CLS has been observed in multiple disease settings, the most common being sepsis. In Oncology, CLS has been reported more often as a complication from therapy, and less often from malignancy. In this case study, we documented clinical manifestation, laboratory features and radiological findings of CLS from rituximab therapy when employed in combination with a multi-agent chemotherapy regimen (EPOCH-R). Differentiating drug-induced CLS from sepsis, which presents with the same clinical features, is important in avoiding further exposure to rituximab, which could be fatal to the patient.