Effects of the AMPAR Antagonist, Perampanel, on Cognitive Function in Rats Exposed to Neonatal Iron Overload.

Iron accumulation has been associated with the pathogenesis of neurodegenerative diseases and memory decline. As previously described by our research group, iron overload in the neonatal period induces persistent memory deficits and increases oxidative stress and apoptotic markers. The neuronal insult caused by iron excess generates an energetic imbalance that can alter glutamate concentrations and thus trigger excitotoxicity. Drugs that block glutamatergic receptor eligibly mitigate neurotoxicity; among them is perampanel (PER), a reversible AMPA receptor (AMPAR) antagonist. In the present study, we sought to investigate the neuroprotective effects of PER in rats subjected to iron overload in the neonatal period. Recognition and aversive memory were evaluated, AMPAR subunit phosphorylation, as well as the relative expression of genes such as GRIA1, GRIA2, DLG4, and CAC, which code proteins involved in AMPAR anchoring. Male rats received vehicle or carbonyl iron (30 mg/kg) from the 12th to the 14th postnatal day and were treated with vehicle or PER (2 mg/kg) for 21 days in adulthood. The excess of iron caused recognition memory deficits and impaired emotional memory, and PER was able to improve the rodents' memory. Iron increased the phosphorylation of GLUA1 subunit, which was reversed by PER. Furthermore, iron overload increased the expression of the GRIA1 gene and decreased the expression of the DLG4 gene, demonstrating the influence of metal accumulation on the metabolism of AMPAR. These results suggest that iron can interfere with AMPAR functionality, through altered phosphorylation of its subunits, and the expression of genes that code for proteins critically involved in the assembly and anchoring of AMPAR. The blockade of AMPAR with PER is capable of partially reversing the cognitive deficits caused by iron overload.

Perampanel-induced hair curling in a patient with epilepsy associated with Pitt Hopkins syndrome.

Antiepileptic drug side effects are frequent, 42% of them corresponding to cosmetic changes. The most frequent effects are weight gain, gingival hyperplasia, and hair loss. Hair changes in texture or colour are rarely reported in the literature. We present a case of hair curling after the introduction of perampanel. A 13-year-old girl with genetically confirmed Pitt-Hopkins syndrome with uncontrolled seizures, while on treatment with levetiracetam and valproic acid, was started on perampanel, reaching seizure control. After a few weeks of the introduction of the new antiepileptic drug, she developed hair curling. Hair curling is a rare cosmetic side effect, reported mainly in patients under valproic acid treatment. Perampanel is a recently introduced pharmaceutical molecule with no prior reports of hair changes as a side effect. There is no clear explanation for this side effect, but it should be discussed with patients taking valproate whenever perampanel is added to the treatment.

Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome.

Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptoms, recent international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand. In fact, the most effective preventive strategy involves not using dopaminergic agents unless absolutely necessary. Indeed, should dopaminergic treatment be needed to handle the symptoms effectively, then it is recommended that the dopaminergic load be reduced by using the lowest effective dose for the shortest possible period of time. However, it must be taken into account that the only α2δ ligand approved for RLS/WED is gabapentin enacarbil, which is not yet available in Europe. Furthermore, recent studies have also reported on the efficacy of opioids as a second-line treatment of RLS/WED, following treatment failure with dopamine agonists. Recent guidelines have taken these new data into account and highlight that a low dose of an opioid (prolonged-release oxycodone or methadone) may be considered in patients with very severe augmentation of symptoms. Alternative non-dopaminergic treatment concepts based on glutamatergic and adenosinergic mechanisms are currently in development, and are likely to provide encouraging therapeutic alternatives.