Maria Luisa Mancini

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=−0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid.

The study set out to investigate the role of corticotrophin-releasing factor (CRF) and orexin-A in chronic migraine (CM) and medication-overuse headache (MOH). Twenty-seven patients affected by CM and 30 with MOH were enrolled. Control CSF specimens were obtained from 20 age-matched subjects who underwent lumbar puncture for diagnostic purposes, and in all of them CSF and blood tests excluded central nervous system or systemic diseases. Orexin-A and CRF were determined by radioimmunoassay methods. Significantly higher levels of orexin-A and CRF were found in the CSF of MOH and to a lesser extent in patients with CM compared with control subjects (orexin-A: P < 0.001 and P < 0.02; CRF: P < 0.002 and P < 0.0003). A significant positive correlation was also found between CSF orexin-A values and those of CRF (R = 0.71; P < 0.0008), monthly drug intake group (R = 0.39; P < 0.03) and scores of a self-completion 10-item instrument to measure dependence upon a variety of substances, the Leeds Dependence Questionnaire (LDQ) in the MOH group (R = 0.68; P < 0.0003). The significantly higher orexin-A levels found in CM and MOH can be interpreted as a compensatory response to chronic head pain or, alternatively, as an expression of hypothalamic response to stress due to chronic pain. A potential role for orexin-A in driving drug seeking in MOH patients through activation of stress pathways in the brain can also be hypothesized.

Obsessive-Compulsive Disorder and Migraine With Medication-Overuse Headache

Objective.— A strong association has been demonstrated between migraine, particularly in the chronic form and with medication overuse, and either major depression or various anxiety disorders. However, there has been less systematic research on the links between migraine with medication‐overuse headache (MOH) and obsessive‐compulsive disorder (OCD). A drug‐seeking behavior shares with OCD the compulsive quality of the behavior. We investigated the relationship between OCD and MOH in migraineurs.

NF‐κB activity and iNOS expression in monocytes from internal jugular blood of migraine without aura patients during attacks

This study investigated nuclear factor-kappa B (NF-κB) activity by electrophoresis mobility gel shift assay and IκBα expression by Western blot analysis in monocytes obtained from serial samples of internal jugular venous blood taken from seven migraine patients without aura during attacks. Inducible nitric oxide synthase (iNOS) expression was also assessed by reverse transcription-polymerase chain reaction. An increase in NF-κB activity peaked 2 h after attack onset. This was accompanied by a transient reduction in IκBα expression. Up-regulation of iNOS was evident at 4 h, maintained at 6 h and reduced at the end of the attack. These findings substantiate the hypothesis of transitory delayed inflammation, as suggested by the animal model, and suggest the possibility of using therapeutic approaches to target NF-κB transcription in the treatment of migraine.

Prevalence of essential tremor in the territory of Lake Trasimeno, Italy: Results of a population-based study

Because of the great variability in previous epidemiological data, and in light of the more accurate definition and diagnostic criteria recently formulated, we designed the present study to evaluate the prevalence of essential tremor (ET) in an Italian population. The study population included 13,604 individuals, who represented all patients of 11 family doctors working in the Territory of Lake Trasimeno in central Italy. Assessment of the sample and selection of the suspected cases were carried out by the same family doctors, previously trained to apply the inclusion and exclusion criteria for the definition of ET based on the Classification Criteria of the Movement Disorder Society (1998) and the Guidelines of the Ad Hoc Committee (2000). The total population was assessed over a period of 12 months. The age‐adjusted prevalence of ET was 1.21% (95% confidence interval, 0.83–1.76). The probability of presenting with ET tended to increase with age and males showed a 50% greater risk for developing ET (male/female ratio = 1.5 for each age class). Our results are in line with the most recent epidemiological findings, which suggest a lower prevalence of ET than in older studies. These results can be attributed to the application of more stringent diagnostic criteria.

Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinsons Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.

Practical Considerations for the Treatment of Elderly Patients with Migraine

Treatment of migraine presents special problems in the elderly. Co-morbid diseases may prohibit the use of some medications. Moreover, even when these contraindications do not exist, older patients are more likely than younger ones to develop adverse events. Managing older migraine patients, therefore, necessitates particular caution, including taking into account possible pharmacological interactions associated with the greater use of drugs for concomitant diseases in the elderly.Paracetamol (acetaminophen) is the safest drug for symptomatic treatment of migraine in the elderly. Use of selective serotonin 5-HT1B/1D receptor agonists (‘triptans’) is not recommended, even in the absence of cardiovascular or cerebrovascular risk, and NSAID use should be limited because of potential gastrointestinal adverse effects.Prophylactic treatments include antidepressants, β-adrenoceptor antagonists, calcium channel antagonists and antiepileptics. Selection of a drug from one of these classes should be dictated by the patient’s co-morbidities. β-Adrenoceptor antagonists are appropriate in patients with hypertension but are contraindicated in those with chronic obstructive pulmonary disease, diabetes mellitus, heart failure and peripheral vascular disease. Use of antidepressants in low doses is, in general, well tolerated by elderly people and as effective, overall, as in young adults. This approach is preferred in patients with concomitant mood disorders. However, prostatism, glaucoma and heart disease make the use of tricyclic antidepressants more difficult. Fewer efficacy data in the elderly are available for selective serotonin reuptake inhibitors, which can be tried in particular cases because of their good tolerability profile. Calcium channel antagonists are contraindicated in patients with hypotension, heart failure, atrioventricular block, Parkinson’s disease or depression (flunarizine), and in those taking β-adrenoceptor antagonists and monoamine oxidase inhibitors (verapamil). Antiepileptic drug use should be limited to migraine with high frequency of attacks and refractoriness to other treatments. Promising additional strategies include ACE inhibitors and angiotensin II type 1 receptor antagonists because of their effectiveness and good tolerability in patients with migraine, particularly in those with hypertension. Because of its favourable compliance and safety profile, botulinum toxin type A can be considered an alternative treatment in elderly migraine patients who have not responded to other currently available migraine prophylactic agents.Pharmacological treatment of migraine poses special problems in regard to both symptomatic and prophylactic treatment. Contraindications to triptan use, adverse effects of NSAIDs, and unwanted reactions to some antiemetics reduce the list of drugs available for the treatment of migraine attacks in elderly patients. The choice of prophylactic treatment (β-adrenoceptor antagonists, calcium channel antagonists, antiepileptics, and more recently, some antihypertensive drugs) is influenced by co-morbidities and should be directed at those drugs that are believed to have fewer adverse effects and a better safety profile. Unfortunately, for most of these drugs, efficacy studies are lacking in the elderly.

Language disturbances as a side effect of prophylactic treatment of migraine.

Background.— Language disturbances have been previously described as word‐finding difficulties in epileptic patients. These disturbances have been recently reported in migraineurs in treatment with topiramate but they have never been defined and assessed in these patients with the aid of neuropsychological testing.

Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.

Memantine alters striatal plasticity inducing a shift of synaptic responses toward long-term depression

Memantine is an open channel blocker that antagonizes NMDA receptors reducing the inappropriate calcium (Ca(2+)) influx occurring in presence of moderately increased glutamate levels. At the same time, memantine has the ability to preserve the transient physiological activation of NMDA receptor, essential for learning and memory formation at synaptic level. In the present study we investigated the effects exerted by memantine on striatal synaptic plasticity in rat striatal spiny projection neurons (SPNs). In vitro application of memantine in striatal slices elicited a disruption of long-term potentiation (LTP) induction and maintenance, and revealed, in the majority of the recorded neurons, a long-term depression (LTD), whose amplitude was concentration-dependent (0.3-10 μM). Interestingly, preincubation with the dopamine (DA) D2 receptor antagonist sulpiride (10 μM) prevented memantine-induced LTD and restored LTP. Moreover, the DA D2 agonist quinpirole (10 μM), similarly to memantine, induced LTD in a subgroup of SPNs. In addition, memantine-induced LTD was also prevented by the CB1 endocannabinoid receptor antagonist AM 251 (1 μM). These results suggest that the actions exerted by memantine on striatal synaptic plasticity, and in particular the induction of LTD observed in SPNs, could be attributed to its ability to activate DA D2 receptors. By contrast, blockade of NMDA receptor is not involved in memantine-induced LTD since APV (30 μM) and MK801 (10 μM), two NMDA receptor antagonists, failed to induce this form of synaptic plasticity. Our data indicate that memantine could be used as treatment of neurological disorders in which DA D2 receptor represents a possible therapeutic target.