313 research outputs found
Genistein, a soy isoflavone, reverses mechanical allodynia and oxidative and inflammatory stress in a diabetic mouse model of neuropathic pain
No full textAntinociceptive activity of soy isoflavone genistein in murine models of diabetes- and nerve injury-induced painful neuropathy : involved mechanisms
No full textNeuropathic pain occurs secondarily to CNS injury or, more commonly, in association with injury to the PNS. These injuries can be caused by tumours compressing peripheral nerves, toxins used in chemotherapy, metabolic disease (diabetes), viral disease (Herpes Zoster), severe ischemic insults, trauma and disc herniations that stretch, compress or inflame a nerve root but, despite more than 40 years of research, there are still non-effective treatments. The typical pharmacological treatments for neuropathic pain of any origin are anti-depressant, anti-convulsant or topical agents; also opiates are often ineffective. There is therefore a need for new drugs that act not only on central and peripheral neuronal component, but also on immune cells.
There is great interest in soy isoflavones as alternatives to endogenous estrogens not only in hormonal pathologies, but also in inflammatory, neurodegenerative diseases and pain, so we examined the therapeutic effect of genistein, the major isoflavone in soy, against painful hypersensitivity in two models of murine peripheral neuropathy: a mononeuropathy, induced by the chronic constriction injury (CCI) of sciatic nerve, and a diabetic polyneuropathy, induced by a injection of a pancreatic -cell citotoxin, streptozotocin (STZ). Genistein, the major natural phytoestrogen isoflavone in soybean, has a weak estrogenic effect and a well-known non-specific tyrosine kinase inhibitory activity at pharmacological doses. It has 7-30 times less binding affinity for estrogen receptor (ER) α than ERβ, and is therefore devoid of unwanted severe ERα agonist side effects, such as cancer promotion. It also has effects that are independent of its estrogenic activity, including protein tyrosine kinase inhibition or down-regulation, immune system modulation and anti-oxidant activity. Finally, over the last few years, public and scientific interest in phytoestrogens has increased because of their proposed neuroprotective effects against neurodegenerative diseases, neuronal damage, cerebral stroke and ischemia.
The peripheral mononeuropathy, which is based on the unilateral loose ligation of sciatic nerve, simulates the human clinical condition of chronic nerve compression, such as the one that occurs in nerve entrapment neuropathy or spinal roots irritation by a lumbar disk erniation and was induced by right sciatic nerve CCI according to Bennett and Xie; diabetes was induced by a single injection of STZ (120 mg/kg, i.p.) and both models were studied in C57BL/6J adult male mice.
Neuropathies are frequently associated with allodynia (pain to innocuous stimuli) and hyperalgesia (a heightened pain response generated by a painful stimulus); we evaluated changes in paw withdrawal thresholds with Von Frey filament and Plantar test. A treatment regimen with greater clinical applicability would involve compounds that are efficacious at reversing neuropathic pain symptoms once they are established, so three days after CCI and 14 days after STZ injection, genistein was injected subcutaneously (1-30 mg/kg) daily for 11 days and over three weeks, respectively. The isoflavone repeated administration reversed in time and dose-relared fashion thermal hyperalgesia and mechanical allodynia in nerve injured mice and mechanical allodynia in diabetic mice. Surely classical estrogen receptors (ER), particularly ERβ, are involved in phytoestrogen antinociceptive activity in CCI model, in fact a specific ERβ antagonist prevented both its anti-allodynic and anti-hyperalgesic action, whereas a specific ERα antagonist was ineffective and a non-selective ER antagonist only reversed the anti-allodynic effect. It is worth bearing in mind that genistein binds ER with higher affinity for the ERβ, that are particulary present in neurons, microglia, astrocytes, Schwann cells and immune cells, but less expressed than ER in estrogen-dependent tissues.
In pathological nociceptive disorders, particularly in the induction of painful peripheral neuropathy, reactive radical species are generated in excess and consequently create oxidative stress in tissues; oxidative stress is the result of an imbalance between the reactive oxygen and nitrogen species and antioxidant compounds. Antioxidant effects are implicated in the antinociceptive genistein activity, since the efficacious doses on painful hypersensitivity, simoultaneusly reversed the increase in the ROS and malondialdeyde tissue levels and increased or restored the activity of antioxidant enzymes and the ratio between reduced and oxidized glutathione content.
Neuropathic pain is partially mediated by neuroinflammatory mechanisms and it also modulates local neurogenic inflammation. In fact, the release of inflammatory mediators from immune and glial cells in either peripheral and CNS may have an important role in the development and the manteinance of the neuropathic pain physiopathological processes. Genistein efficacy on pain sintomatology was due also to its neuroimmunomodulatory and anti-inflammatory properties, since in peripheral and central nervous system steps involved in pain development and trasmission (the sciatic nerve proximal to the trifurcation, the L4, L5 and L6 dorsal root ganglia, the lumbar dorsal spinal cord, at the same level, and the thalamus) the phytoestrogen reduced nuclear factor-κB, nitric oxide system and proinflammatory cytokine overactivation in both peripheral neuropathy models.
In conclusion these results suggest that soy isoflavone genistein ameliorates the CCI- and diabetes-induced nociceptive hypersensitivity by its antioxidant, antiinflammatory and neuroimmunomodulatory properties and it represents a possible therapeuthic hope to treat neuropathic pain that is still now devoid of satisfactorily effective treatments
Transient early expression of TNF-alfa in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy
No full textThe proinflammatory cytokine tumor necrosis factor-α (TNF) is an important mediator in neuropathic pain. We investigated the temporal pattern of TNF mRNA expression in the sciatic nerve, in dorsal root ganglia (DRG) and spinal cord in the mouse chronic constriction injury model of neuropathy with quantitative real-time polymerase chain reaction. Neuropathic pain-like behaviour was monitored by evaluating thermal hyperalgesia and mechanical allodynia. Pain-related behaviour and TNF expression were evaluated 6 h, 1, 3, 7 and 14 days after injury. Naive animals and sham-operated mice were used as controls. We found an early upregulation of sciatic nerve TNF mRNA levels in chronic constriction injury (CCI) and sham-operated animals 6 h after surgery: 1 day later TNF overexpression was present in CCI mice only and disappeared 3 days after injury. The mRNA cytokine levels were elevated in DRG 1 and 3 days after surgery in CCI animals only, while the cytokine was not modulated in the spinal cord. A significant hyperalgesia was present in CCI and sham-operated mice at 6 h and 1 day, while at later time point only CCI mice presented lower thresholds. Mechanical allodynia was already present only in CCI animals 6 h from surgery and remained constant up to the 14th day. The results indicate that a transient early TNF upregulation takes place in peripheral nervous system after CCI that can activate a cascade of proinflammatory/pronociceptive mediators
Mechanisms involved in the reversal phytoestrogen genistein-evocated nociceptive hypersensitivity in a mouse neuropathy model induced by chronic constriction injury
No full textPhytoestrogen genistein reduces nociceptive hypersensitivity in the mouse chronic constriction injury model
No full textTherapeutic effect of purinergic antagonism in nociceptive hypersensitivity following to mouse mononeuropathy : peripheral and central involved mechanisms
No full textGenistein, a natural phytoestrogen from soy, relieves neuropathic pain following chronic constriction sciatic nerve injury in mice : anti-inflammatory and antioxidant activity
No full textThere is great interest in soy isoflavones as alternatives to endogenous estrogens not only in hormonal pathologies, but also in inflammatory, neurodegenerative diseases and pain. We investigated the effect of the isoflavone genistein on neuropathic pain. Genistein binds estrogen receptors (ER) with higher affinity for the ERbeta particularly expressed in neuronal and immune cells. Neuropathy was induced in mice by means of chronic sciatic nerve constriction, and the subcutaneous administration of genistein from the third day after the lesion reversed pain hypersensitivity in a time- and dose-dependent manner. This effect may have been due to the activation of classical nuclear receptor and/or anti-oxidant, anti-inflammatory and immunomodulating properties of genistein. The fact that a specific ERbeta antagonist prevented both its anti-allodynic and anti-hyperalgesic action, whereas a specific ERalpha antagonist was ineffective and a non-selective ER antagonist only reversed the anti-allodynic effect, suggests the involvement of ERbeta. Antioxidant effects are also involved as the anti-nociceptive dose reversed the increase in reactive oxygen species and malondialdehyde in injured paw tissues, and increased the activity of anti-oxidant enzymes. The phytoestrogen had immunomodulatory and anti-inflammatory activities as it reduced peripheral and central nuclear factor-small ka, Cyrillicappa B, nitric oxide system and pro-inflammatory cytokine over-activation. Taken together, our results suggest that genistein could ameliorate painful neuropathy by multiple mechanisms
Anthyhyperalgesic and antiallodynic effect of purinergic antagonists in a mouse model of mononeuropathy : neuroinflammatory involved mechamisms
No full textThe soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotrophic and vasculature deficits in diabetes mouse model
No full textTreatment of diabetes complications remains a substantial challenge. The aim of this study was to explore the ability of the soy isoflavone genistein in attenuating the signs that follow diabetes onset: nociceptive hypersensitivity, oxidative and inflammatory state, nerve growth factor (NGF) decrease and vascular dysfunctions. Genistein (3 and 6 mg/kg) was administered to C57BL/6J streptozotocin diabetic mice from the 2nd till the 5th week after disease induction. The hind paw withdrawal threshold to mechanical stimulation (tactile allodynia) was evaluated by a von Frey filament. The oxidative stress was assessed measuring: reactive oxygen species by fluorimetric analysis, both the lipoperoxide content, as malondialdehyde, the antioxidant enzymatic activities spectrophotometrically and the glutathione content spectrofluorimetrically. Proinflammatory cytokines and NGF were measured in the sciatic nerve by enzyme-linked immunosorbent assay. Aortic inducible (iNOS) and endothelial nitric oxide synthase (eNOS) protein content was measured by western immunoblotting. Genistein relieved diabetic peripheral painful neuropathy, reverted the proinflammatory cytokine and reactive oxygen species overproduction, and restored the NGF content in diabetic sciatic nerve. Furthermore it restored the GSH content and the GSH and GSSG ratio, improved the antioxidant enzymes activities, decreased reactive oxygen species and lipoperoxide level in the brain and liver. Finally it restored the iNOS and eNOS content and the superoxide dismutase activity in thoracic aorta. Hyperglycaemia and weight decrease were not affected. Genistein is able to reverse a diabetes established condition of allodynia, oxidative stress and inflammation, ameliorates NGF content and the vascular dysfunction, thus suggesting its possible therapeutic use for diabetes complications
Due nuove specie del genereGenistaL. nel Mediterraneo
No full textThe author describes two new species ofGenistarecorded in some areas of central Mediterranean basin
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