Abstract
BackgroundMice with pilocarpine-induced temporal lobe epilepsy (TLE) are characterized by intense hippocampal neuroinflammation, a prominent pathological hallmark of TLE that is known to contribute to neuronal hyperexcitability. Recent studies indicate that Adam10, a member of a disintegrin and metalloproteinase domain-containing protein (Adam) family, has been involved in the neuroinflammation response. However, it remains unclear whether and how Adam10 modulates neuroinflammation responses in the context of an epileptic brain or whether Adam10 affects epileptogenesis via the neuroinflammation pathway.MethodsAdult male C57BL/6J mice were subjected to intraperitoneal injection of pilocarpine to induce TLE. Adeno-associated viral (AAV) vectors carrying Adam10 (AAV-Adam10) or lentiviral vectors carrying short hairpin RNA, which is specific to the mouse Adam10 mRNA (shRNA-Adam10), were bilaterally injected into the hippocampus to induce overexpression or knockdown of Adam10, respectively. The specific anti-inflammatory agent minocycline was administered following status epilepticus (SE) to block hippocampal neuroinflammation. Continuous video EEG recording was performed to analyze epileptic behavior. Western blot, immunofluorescence staining, and ELISA were performed to determine Adam10 expression as well as hippocampal neuroinflammation.ResultsIn this study, we demonstrate that overexpression of Adam10 in the hippocampus suppresses neuroinflammation and reduces seizure activity in TLE mice, whereas knockdown of Adam10 exacerbates hippocampal neuroinflammation and increases seizure activity. Furthermore, increased seizure activity in Adam10 knockdown TLE mice is dependent on hippocampal neuroinflammation.ConclusionThese results suggest that Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation. Our findings provide new insights into the Adam10 regulation of development of epilepsy via the neuroinflammation pathway and identify a potential therapeutic target for epilepsy.
Highlights
Mice with pilocarpine-induced temporal lobe epilepsy (TLE) are characterized by intense hippocampal neuroinflammation, a prominent pathological hallmark of TLE that is known to contribute to neuronal hyperexcitability
Adam10 has been largely distributed in the astrocytes [15, 16], as well as neurons [17], and it has been found to be responsible for proteolytic processing of CX3CL1, a chemokine primarily expressed in the neurons and astrocytes, which is involved in the neuroinflammation response [16]
Adam10 expression is decreased in the hippocampus of pilocarpine-induced status epilepticus (SE) mice A growing body of evidence suggests a possible link between Adam10 and epilepsy [8, 10, 23, 24]
Summary
Mice with pilocarpine-induced temporal lobe epilepsy (TLE) are characterized by intense hippocampal neuroinflammation, a prominent pathological hallmark of TLE that is known to contribute to neuronal hyperexcitability. Recent studies indicate that Adam, a member of a disintegrin and metalloproteinase domain-containing protein (Adam) family, has been involved in the neuroinflammation response It remains unclear whether and how Adam modulates neuroinflammation responses in the context of an epileptic brain or whether Adam affects epileptogenesis via the neuroinflammation pathway. It is generally accepted that neuroinflammation is a prominent pathological hallmark of TLE, which is known to contribute to neuronal hyperexcitability in both human patients and animal models [11,12,13,14] These studies indicate that seizure-induced proinflammatory signals may play a pivotal role in recurrent epilepsy. In the present study, we sought to explore the role of Adam in neuroinflammation of the epileptic brain and to further determine whether Adam affects epileptogenesis through neuroinflammation pathways
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