AMPA receptor antagonists(University of Messina)

Stroke patients often experience multiple functional impairments, including difficulties with swallowing, speech, cognition, and motor skills, which can lead to symptoms such as emotional distress and cognitive deficits. Approximately one-third of post-stroke patients may develop poststroke depression (PSD), significantly hindering recovery and increasing the burden on families and healthcare systems. This review focuses on the underlying mechanisms of PSD, emphasizing the glutamatergic hypothesis. As the primary excitatory neurotransmitter, glutamate plays a central role in neural-signaling. However, excessive glutamate accumulation can cause neuronal damage, making it a key mechanism in the development of PSD. Astrocytes are crucial for maintaining glutamate homeostasis by clearing excess glutamate and regulating its synthesis and transport, thereby preventing excitotoxicity. Following a stroke, astrocytic dysfunction—characterized by overactivation and inflammatory responses—can exacerbate neuronal injury and further contribute to the emergence of depressive symptoms. This article also highlights potential therapeutic approaches targeting the glutamatergic system, such as NMDA receptor antagonists, AMPA receptor antagonists, and modulators of glutamate transporters, as well as other types (e.g., Chinese medicine, herbal medicine, and targeted pathways acting on neurons). These strategies offer promising avenues for PSD treatment. Future studies should delve deeper into the molecular mechanisms by which astrocytes regulate glutamate homeostasis, providing a robust foundation for the precision treatment of post-stroke depression.

Antiseizure medications (ASMs), which may influence cortical excitability, are the mainstay of epilepsy treatment. Transcranial magnetic stimulation (TMS) helps evaluate cortical excitability. We assessed changes in TMS responses using serial TMS measurements in people treated with an adjunctive noncompetitive AMPA‐receptor antagonist.

We included adults with refractory, active epilepsy (≥ 1 seizure/month), advised to start adjunctive treatment with the noncompetitive AMPA‐receptor antagonist perampanel as outpatients. After informed consent, we performed TMS measurement at three points: baseline before starting perampanel, at around 2 months after starting (4 mg/day), and at a final/effective dose around 6 months. Dependent on seizure reduction (> 50%), participants were dichotomized into responders (Rs) and nonresponders (NRs). We compared changes in motor cortex excitability through the rMT using a linear mixed‐effects model. We evaluated TMS‐evoked potentials (TEPs) to single pulse and paired pulse using within‐subject Monte Carlo–based permutation analysis.

We included 18 adults, of whom 17 (6 R, 11 NR, 1 lost to follow‐up) had baseline and second‐month measurements, and nine (4 R, 5 NR) had all three. In responders, motor cortex excitability, quantified by rMT, significantly increased with increasing dose. Conversely, no significant changes were seen in the NR subgroup. TEPs for the single pulse and paired pulse showed no significant clusters for any peaks between measurement and group comparisons.

The TEPs showed no significant changes between measurements and/or groups. Motor cortex excitability quantified by rMT is a potential biomarker to track or predict treatment outcomes in people starting adjunctive perampanel for epilepsy.