Laura Rombolà

Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat.

Recent studies support a role for excitotoxicity in the development of retinal ganglion cell (RGC) damage in subjects suffering from glaucoma. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, has been reported to afford neuroprotection, preventing the formation of the mitochondrial permeability transition pore. Using an established animal model of retinal ischemia/reperfusion here, we show that synaptic glutamate increases at 130min from beginning of reperfusion and delayed apoptosis in the RGC layer is seen at 24h. Intraocular administration of CoQ10 minimizes glutamate increase and affords neuroprotection, suggesting that oxidative stress and energy failure might be implicated in the mechanisms of RGC death.

Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca(2+) current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.SWDs were immediately and substantially reduced (approximately 90%) by systemic administration of ETX (177-709 micromol/kg), or by bilateral microinfusion into the thalamus of the GABA(B) antagonist, CGP 36742 (5-27 nmol per side). However, infusion of ETX (1-200 nmol per side) into the ventrobasal complex or the NRT resulted in a reduction of SWDs that was delayed (30-60 min) and less marked (approximately 50%). Administration of ETX (0.2 mM to 1M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1mM. Only at 5mM were seizures significantly reduced (approximately 70%) within 30 min of administration. These results suggest that targeting of the thalamus alone may be insufficient for an immediate and full anti-absence action for ETX. Concomitant or exclusive actions in the cortex remain a possibility.

Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection.

Glaucoma is a worldwide leading cause of irreversible vision loss characterized by progressive death of retinal ganglion cells (RGCs). In the course of glaucoma, RGC death may be the consequence of energy impairment that triggers secondary excitotoxicity and free radical generation. There is substantial evidence also that a number of free radical scavengers and/or agents that improve mitochondrial function may be useful as therapies to ameliorate cell death in various neurological disorders including glaucoma. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, has been reported to afford neuroprotection in neurodegenerative diseases, such as Alzheimers and Parkinsons diseases, and its protective effect has been attributed in part to its free radical scavenger ability and to a specific regulation of the mitochondrial permeability transition pore. Using an established animal model of transient retinal ischemia, we have conclusively identified a role for abnormal elevation of extracellular glutamate in the mechanisms underlying RGC death that occurs, at least in part, via activation of the apoptotic program. Under these experimental conditions, N-methyl-D-aspartate (NMDA) and non-NMDA subtype of glutamate receptor antagonists, nitric oxide synthase inhibitors, and CoQ10 afford retinal protection supporting an important role for excitotoxicity in the mechanisms underlying RGC death.

Implication of limonene and linalyl acetate in cytotoxicity induced by bergamot essential oil in human neuroblastoma cells.

Bergamot (Citrus bergamia, Risso et Poiteau) essential oil (BEO) is a widely used plant extract showing anxiolytic, analgesic and neuroprotective effects in rodents; also, BEO activates multiple death pathways in cancer cells. Despite detailed knowledge of its chemical composition, the constituent/s responsible for these pharmacological activities remain largely unknown. Aim of the present study was to identify the components of BEO implicated in cell death. To this end, limonene, linalyl acetate, linalool, γ-terpinene, β-pinene and bergapten were individually tested in human SH-SY5Y neuroblastoma cultures at concentrations comparable with those found in cytotoxic dilutions of BEO. None of the tested compounds elicited cell death. However, significant cytotoxicity was observed when cells were cotreated with limonene and linalyl acetate whereas no other associations were effective. Only cotreatment, but not the single exposure to limonene and linalyl acetate, replicated distinctive morphological and biochemical changes induced by BEO, including caspase-3 activation, PARP cleavage, DNA fragmentation, cell shrinkage, cytoskeletal alterations, together with necrotic and apoptotic cell death. Collectively, our findings suggest a major role for a combined action of these monoterpenes in cancer cell death induced by BEO.

Opioids Resistance in Chronic Pain Management

Abstract: Chronic pain management represents a serious healthcare problem worldwide. Chronic pain affects approximately 20% of the adult European population and is more frequent in women and older people. Unfortunately, its management in the community remains generally unsatisfactory and rarely under the control of currently available analgesics. Opioids have been used as analgesics for a long history and are among the most used drugs; however, while there is no debate over their short term use for pain management, limited evidence supports their efficacy of long-term treatment for chronic non-cancer pain. Therapy with opioids is hampered by inter-individual variability and serious side effects and some opioids often result ineffective in the treatment of chronic pain and their use is controversial. Accordingly, for a better control of chronic pain a deeper knowledge of the molecular mechanisms underlying resistance to opiates is mandatory.

Caspase-1-independent Maturation of IL-1β in Ischemic Brain Injury: is there a Role for Gelatinases?

Ischemic stroke is a devastating condition primarily caused by reduced blood supply to the brain. Interleukin (IL)-1β is a pro-inflammatory cytokine that plays a pivotal role in the detrimental inflammatory processes that participate to cerebral ischemic damage. After injury, it is produced by distinct cells of the neurovascular unit as an inactive precursor, pro-IL-1β. Although previous studies have suggested that caspase-1 is the main enzyme implicated in the cleavage of pro-IL-1β into the biologically active cytokine, recent work has demonstrated that, under ischemia-reperfusion conditions, other mechanisms may be involved in cytokine maturation. Indeed, we have shown that in rats subjected to transient middle cerebral artery occlusion (MCAo), elevation of IL-1β levels is paralleled by an elevation of gelatinolytic, but not caspase-1 activity in the injured hemisphere and pharmacological inhibition of gelatinases, i.e. matrix metalloproteases (MMP)-2 and MMP-9 prevents cytokine maturation. These findings further support the hypothesis that, under ischemia-reperfusion injury, cerebral elevation of IL-1β occurs via mechanisms other than caspase-1, likely involving gelatinases.

Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats

Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders. However, only limited preclinical evidences are actually available. This study examined the anxiolytic/sedative-like effects of BEO using an open field task (OFT), an elevated plus-maze task (EPM), and a forced swimming task (FST) in rats. This study further compared behavioural effects of BEO to those of the benzodiazepine diazepam. Analysis of data suggests that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of the DZP. The present observations provide further insight to the pharmacological profile of BEO and support its rational use in aromatherapy.

Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain

In complementary medicine, aromatherapy uses essential oils to improve agitation and aggression observed in dementia, mood, depression, anxiety and chronic pain. Preclinical research studies have reported that the essential oil obtained from bergamot (BEO) fruit (Citrus bergamia, Risso) modifies normal and pathological synaptic plasticity implicated, for instance, in nociceptive and neuropathic pain. Interestingly, recent results indicated that BEO modulates sensitive perception of pain in different models of nociceptive, inflammatory and neuropathic pain modulating endogenous systems. Thus, local administration of BEO inhibited the nociceptive behavioral effect induced by intraplantar injection of capsaicin or formalin in mice. Similar effects were observed with linalool and linalyl acetate, major volatile components of the phytocomplex, Pharmacological studies showed that the latter effects are reversed by local or systemic pretreatment with the opioid antagonist naloxone hydrochloride alike with naloxone methiodide, high affinity peripheral μ-opioid receptor antagonist. These results and the synergistic effect observed following systemic or intrathecal injection of an inactive dose of morphine with BEO or linalool indicated an activation of peripheral opioid system. Recently, in neuropathic pain models systemic or local administration of BEO or linalool induced antiallodynic effects. In particular, in partial sciatic nerve ligation (PSNL) model, intraplantar injection of the phytocomplex or linalool in the ipsilateral hindpaw, but not in the contralateral, reduced PSNL-induced extracellularsignal- regulated kinase (ERK) activation and mechanical allodynia. In neuropathic pain high doses of morphine are needed to reduce pain. Interestingly, combination of inactive doses of BEO or linalool with a low dose of morphine induced antiallodynic effects in mice. Peripheral cannabinoid and opioid systems appear to be involved in the antinociception produced by intraplantar injection of β -caryophyllene, present in different essential oils including BEO. The data gathered so far indicate that the essential oil of bergamot is endowed with antinociceptive and antiallodynic effects and contribute to form the rational basis for rigorous testing of its efficacy in complementary medicine.

Natural compounds and retinal ganglion cell neuroprotection

Glaucoma, the second leading cause of blindness in the world, is a chronic optic neuropathy often associated with increased intraocular pressure and characterized by progressive retinal ganglion cell (RGC) axons degeneration and death leading to typical optic nerve head damage and distinctive visual field defects. Although the pathogenesis of glaucoma is still largely unknown, it is hypothesized that RCGs become damaged through various insults/mechanisms, including ischemia, oxidative stress, excitotoxicity, defective axonal transport, trophic factor withdrawal, and neuroinflammation. In this review, we summarize the potential benefits of several natural compounds for RGCs neuroprotection.

Antinociceptive effect of inhalation of the essential oil of bergamot in mice

Bergamot essential oil (BEO) has proven wide evidence of pharmacological antinociceptive effectiveness both in nociceptive and in neuropathic pain models. The antinociceptive properties of BEO for inhalation have not been investigated. The purpose of this study is to evaluate the effects of the inhalation of BEO on formalin-induced nociceptive response in mice. Male ddY-strain mice (Japan SLC, Hamamatsu, Japan) of 23-25 g of weight at the time the experiments underwent the formalin test. Twenty μl of formalin (2% in saline) were administered into the plantar surface of the mice hindpaw and the time of licking/biting was observed and recorded at intervals of 5 min. The device for BEO inhalatory delivery consisted in a filter paper disc soaked with known volume of BEO placed on the edge of the cage. Inhalation of BEO exerted antinociceptive activity. In particular, it reduced the formalin-induced licking/biting behaviour in a manner that was dependent on the volume of BEO used in the device for its release and on the time of exposure to the phytocomplex. The results support the use of BEO in aromatherapy for complementary management of chronic pain relief in a stepwise therapeutic programme.