Ruggero Fariello

The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson's disease

The concentration of neuromelanin (NM) in substantia nigra pars compacta (SNPC) has been measured in male and female normal subjects at different ages in the range 1–97 years old and in SNPC of parkinsonian patients. A very similar age trend of NM concentration was found in both sexes. In the first year of life NM was not detectable, between 10 and 20 years the NM levels were 0.3–0.8 μg/mg of SNPC, between 20 and 50 years were 0.8–2.3 μg/mg SNPC and between 50 and 90 were 2.3–3.7 μg/mg of SNPC. In parkinsonian subjects, the NM levels were 1.2–1.5 μg/mg of SNPC, which is less than 50% with respect to the age‐matched controls. These data demonstrate a continuous NM accumulation in SNPC neurons during aging, the presence of large amounts of NM in SNPC and severe depletion of NM in Parkinsons disease.

Safinamide From molecular targets to a new anti-Parkinson drug

Ideal treatment in Parkinson’s disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential.

Epileptogenic action of intraventricularly injected antimelatonin antibody

In rats, intraventricularly injected antimelatonin antibody caused the appearance of transitory epileptiform abnormalities. Epileptic activity arose from and was limited to the cortical mantle of the hemisphere ipsilateral to the injection side. The occasional occurrence of lateralized seizures has also been observed. Control injection of saline, of the vehicle (rabbit serum), or of antibody saturated with melatonin induced flattening and desynchronization of the electroencephalogram but not epileptiform activity. Repeated antimelatonin injections caused reappearance of the same type of epileptic abnormalities that lasted slightly longer than the first time. Melatonin may play an inhibitory role in neuronal excitability.

Homotaurine (3 aminopropanesulfonic acid; 3APS) protects from the convulsant and cytotoxic effect of systemically administered kainic acid

Pretreatment of rats with homotaurine (3 aminopropanesulfonic acid; 3APS), a synthetic γ-aminobutyric acid (GABA) analog, protected from the convulsant and cytotoxic action of systemically injected kainic acid (KA). Wet dog shaking (WDS) behavior was significantly reduced. Taurine, an inhibitory non-GABA-mimetic amino acid, and muscimol (another direct GABA-agonist) reduced the number of seizures and lesions in the brain but were less effective than homotaurine. Progabide (a GABA-agonist) did not modify kainic acid effects. The neurotoxicity of kainic acid could have been due to repetitive convulsive activity. Activation of GABA-mediated inhibition is an effective, but not the determinant means of preventing KA-induced abnormalities.

PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat.

Kainic acid-induced multifocal status epilepticus in the rat is a model of medically intractable complex partial seizures and neurotoxicity. The exact mechanisms of kainic acid epileptogenic and neurotoxic effects are unknown, but enhanced glutamate release seems to be an important factor. PNU-151774E ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate) is a broad-spectrum new anticonvulsant with Na+ channel-blocking and glutamate release inhibiting properties. We have examined the effect of pretreatment with this compound on both seizure activity and hippocampal neuronal damage induced by systemic injection of kainic acid in rats. Lamotrigine, a recently developed anticonvulsant with similar glutamate release inhibitory properties, was tested for comparison, together with diazepam as reference standard, on the basis of its anticonvulsant and neuroprotectant properties in this animal model. PNU-151774E, lamotrigine (10, 30 mg/kg; i.p.) and diazepam (20 mg/kg; i.p.) were administered 15 min before kainic acid (10 mg/kg; i.p.). In the vehicle-treated group, kainic acid injection caused status epilepticus in 86% of animals. Hippocampal neuronal cell loss was 66% in the CA4 hippocampal area at 7 days after kainic acid administration. Diazepam inhibited both seizures and neurotoxicity. Lamotrigine reduced hippocampal neuronal cell loss at both doses, even when it did not protect from seizures, although it showed a trend toward protection. On the other hand PNU-151774E protected from both hippocampal neurodegeneration and status epilepticus. Thus, these data support the concept that seizure prevention and neuroprotection might not be tightly coupled. Glutamate release inhibition may play a major role in neuroprotection, but an additional mechanism(s) of action might be relevant for the anticonvulsant activity of PNU-151774E in this model.

Pressor response to intravenous tyramine in healthy subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition.

Safinamide is a novel neuroprotectant combining sodium and calcium channel blocking properties with selective, reversible monoamine oxidase type B (MAO B) inhibition. Phase 1 studies have demonstrated that in healthy volunteers, the ED50 (a dose that inhibits enzyme activity by 50% in 50% of treated subjects) for MAO B inhibition is 87.5 &mgr;g/kg/day orally, and that no MAO A inhibition occurs after 10-mg/kg oral dosing. To assess the risk of inducing the “cheese effect,” the effect of safinamide and placebo on the pressor response to tyramine was investigated in a group of healthy male volunteers. The study was an open, single-dose placebo-controlled trial with the 2 treatments in sequence. An increase of 30 mm Hg systolic blood pressure was obtained by intravenous tyramine administered by 0.5-mg incremental boluses injected at 15-minute intervals. The amount of tyramine necessary to achieve such a blood pressure increase was the same after the safinamide 2-mg/kg oral load compared with placebo. These results suggest that dietary restrictions for food with high tyramine content should not be required under safinamide treatment.

Strain differences in convulsive response to the excitotoxin kainic acid.

We describe a strain of rats (Wistar-Furth) that is highly susceptible to the neurotoxic effects of kainic acid (KA) and presents a reliable and quantifiable (with low within-group variability) animal model of status epilepticus. Wistar-Furth rats are more sensitive and demonstrate a less variable convulsant response than Sprague-Dawley and Long-Evans rats when tested for total time in seizure activity, latency to onset of first seizure, latency to status epilepticus, seizure severity scores, and percentage exhibiting behavioral seizures and status epilepticus. Results suggest that significant heterogeneity exists in the rodent population with regard to neuronal sensitivity to an excitotoxic amino acid and indicate that strain differences are an important consideration in studies using KA.

Forebrain influences on an amygdaloid acute focus in the cat

Abstract Amygdaloid activity was recorded in immobilized, artificially ventilated cats, after induction of an acute epileptogenic focus in the nucleus basalis amygdalae followed by electrical stimulation of the head of the caudate nucleus of the medial septal nuclei and of the nucleus accumbens. Septal stimulation at low frequency induced a driving in the amygdaloid spiking, but at high frequency it invariably evoked a seizure. Low frequency caudate stimulation had no detectable effect on amygdala activity even when, by increasing stimulation voltage to 25 V, cortical caudate spindles were elicited. With high-frequency sets (> 30 Hz, > 1.5 V) the caudate exerted a prolonged inhibitory influence on interictal epileptiform activity of the homolateral amygdala. Contrary to the initial effect, a delayed effect was often observed after both septal and caudate stimulation. Accumbens stimulation at low frequency occasionally induced a driving in the focal spiking, but at high frequency had no detectable effect. It is postulated that septal stimulation results in acetylcholine release in the amygdala, and that the different effects of caudate stimulation at various frequencies probably indicate frequency-related preferential activation or inhibition of individual neuronal systems within the caudate nucleus.

Ketamine activation of experimental corticoreticular epilepsy

Generalized corticoreticular epilepsy was established in adult cats by parenteral penicillin, and electroencephalographic monitoring was carried out. Ketamine HCI was injected intravenously in doses of 2.5 to 20 mg per kilogram. If doses of penicillin were inadequate to establish typical spike-wave activity, ketamine induced the spike-wave pattern typical of much higher doses of penicillin. At doses of penicillin that established the spike-wave pattern, ketamine potentiated the spike-wave activity and sometimes induced spike-and-wave status. These findings suggest caution in the clinical use of ketamine in patients with corticoreticular epilepsy. Because analogous effects have been observed upon administration of GABA-mimetic agents, GABA systems may play a role in ketamine anesthesia and corticoreticular epilepsy. Precollicular brain transections failed to modify ketamine effects, excluding a possible influence of mesencephalic centers on the observed potentiation.

Melatonin-induced changes in the sensory activation of acute epileptic foci.

Intraperitoneal, intravenous and intracisternal injection of various amounts (50-1000 microg/kg) of melatonin in cats did not significantly change the focal epileptiform activity produced in various cortical areas and limbic structures by topical application of various convulsant agents. However, when the focus was located in primary sensory areas the sensory evoked activation of the epileptiform activity was reduced or suppressed. The present report and other literature data support the hypothesis that melatonin may change the response of epileptic neurons to sensory stimuli.