Metformin – a Future Therapy for Neurodegenerative Diseases

Abstract

Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer’s disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin’s role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson’s disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin’s advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

“…As noted in the Introduction, the two diseases present abnormal blood glucose levels, insulin resistance, inflammation, oxidative stress, and neurodegeneration [42, 43]. Nowadays, three ChE inhibitors can be used to delay the symptomatic decline observed in patients with AD.…”

“…The importance of selective BuChE inhibition has further been shown using aged rats where BChE inhibition augmented ACh levels, increased cognitive function, and decreased amyloid deposits [50]. Since AChE activity decreases and BuChE activity increases as AD progresses, the inhibition of BuChE may become an increasingly important therapeutic target over time [43]. The principal objective of our studies was to evaluate in a systematic study the mechanism of AChE inhibition by metformin, as even the state-of-the-art scientific literature lacks such knowledge.…”

"Commentary: The ageing as a therapeutic target for Alzheimer's disease"

“…Activation of AMPK-dependent pathways in hNCS's is a potential therapeutic target for AD, because cellular mechanisms of energy homeostasis are connected to AD pathogenesis 34 . Metformin was also found to markedly decrease Beta secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo 35 , thereby reducing BACE1 cleavage products and the production of Aβ. In regard to the beneficial effects of metformin, its anti-inflammatory and antioxidative properties cannot be omitted.…”

Hypoglycemia and the risk of cognitive impairment and dementia in elderly and senile patients with type 2 diabetes

“…Метаанализ показал, что использование метформина у лиц с СД2 было связано с более низким риском развития КН (ОШ 0,55; 95% ДИ 0,38−0,78; р=0,0009), а также деменции и болезни Альцгеймера (ОР 0,76; 95% ДИ 0,60−0,97; р=0,03) по сравнению с лицами с СД2, не получающими метформин. Результаты нескольких клинических исследований зафиксировали положительный эффект метформина на когнитивные функции при болезни Альцгеймера [74][75][76][77]. В литературе имеется несколько публикаций, касающихся изучения механизмов церебропротективных свойств метформина, они включают прямое нейропротективное действие, прежде всего…”

“…антиоксидантное [79, 80, 75,], снижение активности ацетилхолинэстеразы, которая ответственна за деградацию ацетилхолина, нейротрансмиттера, играющего важную роль в процессах обучения и памяти. Помимо этого, при болезни Альцгеймера имеет значение способность метформина снижать активность белка β-секретазы-1, что обуславливает уменьшение содержания продуктов расщепления белкапредшественника β-амилоида и продукцию β-амилоида [74][75][76][77].…”