Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs

Abstract

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABA B antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/ PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology. Elderly individuals with Alzheimer's disease (AD) have about eightfold risk of epileptic seizures compared to age-matched population 1. Moreover, over 40% AD patients with no history of epilepsy show subclinical epileptiform activity in EEG/MEG recordings, which unfavorably influences the disease process 2. This observation raises the question whether this kind of 'silent' epileptic activity needs to be medically treated. However, drug treatment for epileptic activity in AD patients is challenging due to known cognition impairing effects of most anti-epileptic drugs 3. In addition, according to a recent large register study use of anti-epileptic drugs (AEDs) with known cognitive side effects may increase dementia risk in elderly individuals 4. Notably, for most patients in this register study AEDs were prescribed as mood stabilizers for behavioral symptoms, not for detected epileptic activity. So far, no published study has assessed the potential benefit vs. side effects of AEDs or other medication for 'silent' epileptic activity in AD or mild cognitive impairment (MCI) patients. However, there are several ongoing phase 2 clinical trials on cognitive effects of levetiracetam on AD or MCI patients, some of which also include EEG for epileptic activity (NCT04004702, NCT03489044, NCT03875638 at https ://clini caltr ials. gov/ct2/show/). The selection...

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

“…While these findings for seizure worsening with high dose administration of sodium channel blocking ASDs is at first glance concerning for a mouse model of AD, it is well established that sodium channel blockers can lower seizure threshold at high doses [ 76 , 79 ], thus care should be taken to not over interpret these findings as specific to AD models. Lastly, Jin and colleagues have also more recently demonstrated an effect of ESM (200 mg/kg) and LEV (75 mg/kg) on state-dependent spike-wave discharges (SWDs) in aged APP/PS1 mice [ 80 ]. This study highlights the capacity to evaluate the efficacy of ASDs on specific types of epileptiform activity that is also observed in genetically susceptible rat models of absence epilepsy [ 57 , 81 , 82 ].…”

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

“…In contrast, donepezil, a cholinesterase inhibitor had no significant effect on interictal spikes ( 122 ). Another study using the APPswe/PS1dE9 mouse model presenting with spike–wave discharges (SWDs), showed that donepezil does not have a significant effect on epileptic activity whereas atropine decreases SWDs and results in EEG slowing ( 123 ). This information suggests that before the degeneration of cholinergic neurons in AD and DLB, there could be a phase of increased cholinergic tone that contributes to an increase in neuronal activity and epilepsy.…”

Seizure susceptibility in Alzheimer’s disease

“…We have found that an increase in the cortical excitability induced by injection of physostigmine, a reversible cholinesterase inhibitor which increases the ACh level in the brain, increased the frequency of epileptiform-like discharges in APP/PS1 mice 40 . Accordingly, atropine, a muscarinic cholinergic receptor antagonist, significantly decreased epileptiform-like discharge occurrence in APP/PS1 mice 69 .…”