Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

Rojas-Gutierrez, Eduardo; Muñoz-Arenas, Guadalupe; Treviño, Samuel; Espinosa, Blanca; Chávez, Raúl; Rojas, Karla; Flores, Gonzalo; Díaz, Alfonso; Guevara, Jorge

doi:10.1002/syn.21990

Cited by 136 publications

(74 citation statements)

References 304 publications

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“…These encouraging findings let us to investigate whether some of our ANS may optimally exert a neuroprotective action by preventing neuronal death without promoting the cell proliferation that usually represents an undesirable effect hampering the treatment of neurodegenerative processes in various pathological situations, including cancers. Therefore, we compared the ability of our ANS and AP to protect against oxidative stress‐induced neuronal death that is pivotally involved in the patho‐physiological mechanisms of various neurodegenerative disorders . Our results clearly showed that both O‐allyl ANS (BR351 and BR297) had notable advantages over AP with regard to the protection of SH‐SY5Y cells against oxidative stress‐induced death.…”

Section: Discussionmentioning

confidence: 86%

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Taleb

Patte‐Mensah

Meyer

et al. 2018

J Neuroendocrinology

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The neurosteroid allopregnanolone (AP) modulates neuroendocrine/neurobiological processes, including hypothalamic-pituitary-adrenocortical activities, pain, anxiety, neurogenesis and neuroprotection. These observations raised the hope of developing AP-based therapies against neuroendocrine and/or neurodegenerative disorders. However, the pleiotropic actions of AP, particularly its cell-proliferation-promoting effects, hamper the development of selective/targeted therapies. For example, although AP-induced neurogenesis may serve to compensate neuronal loss in degenerative brains, AP-evoked cell-proliferation is contraindicated for steroid-sensitive cancer patients. To foster progress, we synthesised 4 novel AP analogues of neurosteroids (ANS) designated BR053 (12-oxo-epi-AP), BR297 (O-allyl-epi-AP), BR351 (O-allyl-AP) and BR338 (12-oxo-AP). First, because AP is well-known as allosteric modulator of GABAA receptors (GABAA-R), we used the electrophysiological patch-clamp technique to determine the structure-activity relationship of our ANS on GABAA-activated current in NCB20 cells expressing functional GABAA-R. We found that the addition of 12-oxo-group did not significantly change the respective positive or negative allosteric effects of 3α-AP or 3β-(epi)-AP analogues. Importantly, substitution of the 3α-hydroxyl-group by 3α-O-allyl highly modified the ANS activities. Unlike AP, BR351 induced a long-lasting desensitisation/inhibition of GABAA-R. Interestingly, replacement of the 3β-hydroxyl by 3β-O-allyl (BR297) completely reversed the activity from negative to positive allosteric action. In a second step, we compared the actions of AP and ANS on SH-SY5Y neuronal cell viability/proliferation using MTT-reduction assays. Different dose-response curves were demonstrated for AP and the ANS. By contrast to AP, BR297 was totally devoid of cell-proliferative effect. Finally, we compared AP and ANS abilities to protect against oxidative stress-induced neuronal death pivotally involved in neurodegenerative diseases. Both BR351 and BR297 had notable advantages over AP in protecting SH-SY5Y cells against oxidative stress-induced death. Thus, BR297 appears to be a potent neuroprotective compound devoid of cell-proliferative activity. Altogether, our results suggest promising perspectives for the development of neurosteroid-based selective and effective strategies against neuroendocrine and/or neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 86%

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Taleb

Patte‐Mensah

Meyer

et al. 2018

J Neuroendocrinology

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“…[2][3][4] Previously, it has been shown that oxidative stress levels were increased in patients with diabetes mellitus, alzheimer, peripheral vascular diseases, cardiovascular diseases and many chronic diseases. 5,6 It is thought that oxidative stress may increase in the cases of PTC which is not yet clearly identified as etiologically.…”

Section: Dinamik Disülfid Bağ Düzeyi (-S-s-) Ve (-S-s-)/(-sh) (-S-s-mentioning

confidence: 99%

The Relation Between Thiol/Disulphide Homeostasis and Pseudotumor Cerebri

Sariçam¹,

Kömürcü²

2018

Turkiye Klinikleri J Neur

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Section: Opinionmentioning

confidence: 99%

“…However, ACh also suppresses inflammatory system [2], therefore, downregulation of ACh not only causes cognitive dysfunction, but also accelerates inflammatory system. This hyperactivity of inflammatory system is related with various neuropsychiatric disorders including Alzheimer's disease (AD) [3] and depression [4].Moreover, we also speculate this hyperactivity of inflammatory system also induces anticholinergic activity (AA) and this AA accelerates amyloid pathology [5]. Based on this speculation, we propose "the hypothesis of endogenous appearance of AA in AD" [6].…”

mentioning

confidence: 94%

Role of Cholinergic System in Neuropsychiatric Disorders

Hori¹

2017

Anat Physiol

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OpinionNeedless to say acetylcholine (ACh) is relared with cognitive function [1]. However, ACh also suppresses inflammatory system [2], therefore, downregulation of ACh not only causes cognitive dysfunction, but also accelerates inflammatory system. This hyperactivity of inflammatory system is related with various neuropsychiatric disorders including Alzheimer's disease (AD) [3] and depression [4].Moreover, we also speculate this hyperactivity of inflammatory system also induces anticholinergic activity (AA) and this AA accelerates amyloid pathology [5]. Based on this speculation, we propose "the hypothesis of endogenous appearance of AA in AD" [6]. That is, when the downregulation of ACh reaches critical level, AA appears endogenously by way of hyperactivation of inflammatory system and accelerates amyloid pathology [5,6]. Because the factors those cause AA and now reported three other than downregulation of ACh, i.e., medication [7], physical illness [8] and mental stress [9]. Therefore, it is natural that when based on the small amount of deterioration of ACh other AA insert is added, AA also appears [10]. In fact, we showed the patient with AD at MCI level whose serum anticholinergic activity might be positive caused by both small amount of down regulation of ACh and mental stress [11]. Moreover, overburden of cholinergic system might also attribute to the appearance of AA because ACh is no more upregulated in order to compensate for AA insert (upregulation of ACh). Therefore there might be a possibility of the appearance of AA in other disease than AD. We also speculate there might be a possibility of the endogenous appearance of AA in depression and Lewy body disease (LBD). Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and the small amount of downregulation of ACh. It is plausible to conclude that in depression and LBD AA might appear endogenously [12,13]. In depression, the cholinergic system is burdened secondarily to the underlying depressive pathology. During remission, activity of cholinacetyl transferase (ChAT), an enzyme that produces ACh, might be sufficiently upregulated to compensate for the cholinergic burden caused by depressive pathology. However, at the pathological state (depressive state), more upregulation of ACh is not impossible because the ChAT activity is already upregulate. Therefore, in depression there might be a possibility of endogenous appearance of AA [14]. In delirium, we also speculate there might be a possibility of the appearance of AA in delirium. In delirium, increased activity of the HPA axis by exogenous factor, i.e., physical illness, medication or mental stress and the small amount of downregulation of ACh caused by aging or AD, AA also appears.From these considerations we speculate that at least in AD, LBD and depression, the progression of disease might be related with AA at least late sage. Alternatively at late phase of AD, LBD and depression, main pathology might be amyloid pathology. We propose the concept of "anticholinergic spectrum disor...

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Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

Cited by 136 publications

References 304 publications

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

The Relation Between Thiol/Disulphide Homeostasis and Pseudotumor Cerebri

Role of Cholinergic System in Neuropsychiatric Disorders

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