Abstracts

Rationale: Bidirectional connections between Alzheimer’s disease (AD) and epilepsy appear. Diagnosis of diabetes mellitus is associated with a higher risk of developing epilepsy in AD patients. We report (1) partial AD-like phenotype/central insulin resistance in the Wistar Audiogenic Rat (WAR), a genetic epilepsy model, and (2) Facilitation of seizures after intracerebroventricular injections of streptozotocin (icv-STZ; compound mimicking diabetes. We hypothesize that disturbed brain insulin signaling has impact in both epilepsy/AD as one of the main mechanisms connecting the disorders. Goals: (1) To study icv-STZ chemical model of sporadic AD, its effect on audiogenic and sporadic seizure susceptibility, and memory. (2) To analyze effects of metformin (MET), clinically used anti-diabetic drug, on seizure severity/progression/spatial memory in the WAR strain.


Methods: (1) Stereotaxic surgery (Sprague Dawley rats) to implant guiding cannulas/recording electrodes (CEUA-1114/2022R3). Video-EEG of 11 STZ-icv and 10 saline controls, taken before/after injection and on days 7^th and 14^th post-injection, before/during/after acoustic stimulation. On days 21^st and 25^th, 5-day Barnes Maze (BM) test. (2). Adult male WARs (4-6 months old, n=7 per group; CEUA 1293/2024R1), 21-days oral treatment with MET (250 mg/kg). On second day, initiated a chronic high-intensity acoustic stimulus. Brainstem/limbic seizure severity scales were used to analyze seizures progression. On the 14^th day of oral MET treatment, animals underwent the Morris Water Maze (MWM; test of spatial memory).

Results: (1) Icv-STZ significantly altered brain EEG activity (frequencies/regions). On days 7^th and 14^th after icv-STZ, interictal-like activity (isolated spikes/spike-wave complexes) in 54.54% of STZ-icv, not controls (p=0.0085). Spontaneous silent seizures observed only in icv-STZ group (27.27%, ns). Icv-STZ also increased audiogenic seizure susceptibility (seizure scales). On day 7th, mean brainstem scale 0.8 (controls) and 2.273 (icv-STZ) (p=0.0372). On day 14^th, brainstem scale was 0.8 (controls) and 2.636 (icv-STZ) (p=0.0208). In BM test, icv-STZ increased escape latency during training (p=0.0002) and reduced target quadrant occupation in the probe trial (p=0.0195). (2) Seizures less severe in WARs with oral MET, compared to controls, according to both brainstem (P=0.0180) and limbic (P=0.0466) scales. In the MWM test (latency to locate the hidden platform), a main effect of treatment (P=0.0481) was detected. Oral MET performed better in the test, compared to controls.

Conclusions: We reinforce a link between AD and epilepsy through central insulin resistance: (1) impacts of STZ-icv model (brain activity/behavior, alterations in EEG, increased susceptibility to seizures/pronounced spatial memory deficits). (2) Positive modulation of brain insulin signaling (MET) alleviates behavior associated with AD/epilepsy in the WAR strain, underscoring the potential impact of regulating the activity of brain insulin signaling proteins on both disorders.


Funding: FAPESP-17/21155-3, 19/02787-4, 19/05957-8, 19/16574-2, 19/00849-2, 2021/13622-6, INCT-FAPESP-14/50891-1, CNPq-2022-2952, 305883/2014-3-465458/2014-9], CAPES- Finance Code 001-FAEPA.