S100B Inhibitor Pentamidine Attenuates Reactive Gliosis and Reduces Neuronal Loss in a Mouse Model of Alzheimer’s Disease

Abstract

Among the different signaling molecules released during reactive gliosis occurring in Alzheimer's disease (AD), the astrocyte-derived S100B protein plays a key role in neuroinflammation, one of the hallmarks of the disease. The use of pharmacological tools targeting S100B may be crucial to embank its effects and some of the pathological features of AD. The antiprotozoal drug pentamidine is a good candidate since it directly blocks S100B activity by inhibiting its interaction with the tumor suppressor p53. We used a mouse model of amyloid beta- (Aβ-) induced AD, which is characterized by reactive gliosis and neuroinflammation in the brain, and we evaluated the effect of pentamidine on the main S100B-mediated events. Pentamidine caused the reduction of glial fibrillary acidic protein, S100B, and RAGE protein expression, which are signs of reactive gliosis, and induced p53 expression in astrocytes. Pentamidine also reduced the expression of proinflammatory mediators and markers, thus reducing neuroinflammation in AD brain. In parallel, we observed a significant neuroprotection exerted by pentamidine on CA1 pyramidal neurons. We demonstrated that pentamidine inhibits Aβ-induced gliosis and neuroinflammation in an animal model of AD, thus playing a role in slowing down the course of the disease.

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

“…PTM administration has also been shown to ameliorate clinical and/or neuropathologic/biomolecular parameters in other disorders involving the nervous system, such as AD, PD, sepsis-associated encephalopathy, and bowel inflammation, where its action has been reasonably attributed to the block of S100B activity [49][50][51]. In general, variations/manipulations of S100B concentration have been shown to directly correlate with clinical symptoms and/or biomolecular/pathological parameters of these disorders, which depend, as far it is known, on etiologic factors different from those hypothesized for MS, but that share with MS the occurrence of neuroinflammatory processes [5,52].…”

The S100B story: from biomarker to active factor in neural injury

“…), resulted in attenuation of reactive gliosis and neuronal loss in a mouse model of AD induced by Abeta (1‐42) peptide (Cirillo et al . ). In addition, genetic S100B ablation in the presenilin‐1 amyloid precursor protein (PSAPP) double transgenic (APP K670NM671L /PS‐1 M146L ) line, which mimics many facets of human AD, (including plaque deposition, dystrophic neurites, glial activation and memory deficits), has been shown to decrease cortical plaque numbers, reactive astrocytes and microglia, and phospho‐tau positive dystrophic neurons (Roltsch et al .…”

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

“…Moreover, several HMGB1 inhibition approaches, including TTP488, sRAGE-mesenchymal stem cells (MSCs), FPS-ZM1, matrine, pentamidine, hesperidin, and linguizhugan, have revealed promising outcomes in experimental AD models mainly by inhibiting RAGE expression, decreasing production of Aβ, reducing Aβ deposition, oxidative stress, and inflammatory cytokines, while improving spatial learning and memory (Table 2) [113][114][115][116][117][118].…”