Odkrycie farmakologicznego celu leczenia padaczki współwystępującej z chorobą Alzheimera: wgląd w zmiany chemiczne w mózgu na modelu myszy

Despite growing evidences of shared neurochemical alterations linked to comorbid epilepsy in AD, effective unified therapeutic strategies remain lacking. Thus, the present investigation was designed to identify shared neurochemical changes associated with lowered convulsive threshold in STZ (streptozotocin) model of AD-type dementia to pharmacologically address this comorbidity. Swiss albino mice were injected STZ (3 mg/kg, ICV) to induce AD-like pathology. On day 22nd, STZ mice were divided into two groups: one group served as AD control (STZ) and another group (STZ + PTZ) received PTZ (35 mg/kg) kindling to assess the reduced epileptogenesis threshold while naïve served as negative control. One more group was involved as epileptic control (PTZ). All groups underwent behavioral assessment using elevated plus maze, novel object recognition test and radial arm maze. Mice were euthanized on day 48th to collect the brain samples. The brain homogenate was used to assess redox status (GSH, TBARS and ROS), acetylcholinesterase (AChE) activity, amyloid and tau protein expression, histological alterations for specific disease pathology. As well as for neurochemical analysis to assess the shared neurochemical targets associated with comorbid epilepsy in AD. STZ mice were subjected to PTZ kindling exhibited significant greater seizure severity. The kindled status achieved by the sixth injection of PTZ, indicating reduced epileptogenic threshold. Behavioural results indicated significant cognitive impairment in STZ + PTZ treated mice compared with naive mice in EPM, NORT and RAM test. Significantly increased oxidative stress and cholinergic dysfunctions observed in STZ + PTZ mice. Neurochemical analysis revealed augmented excitatory neurotransmitter levels, along with declined glycine, GABA, taurine and arginine in STZ + PTZ mice. Moreover, reduced levels of monoamines and their metabolites reflect cognitive deficits in STZ and STZ + PTZ mice. This increased susceptibility to seizures was accompanied by significantly increased oxidative stress and excitatory neurotransmission in STZ + PTZ mice. Collectively, these observations suggest that AD related neurodegeneration may predispose to epileptogenesis further aggravate neurochemical changes. Our findings suggest that taurine, arginine and monoamines may serve as a shared neurochemical target for comorbid epilepsy in AD-type dementia.