Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a conserved protein, present in plasma and endoplasmic ...reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases.
Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.
Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.
•σ1 Protein agonists (PRE-084, ANAVEX2-73) are neuroprotective and anti-amnesic in Aβ25–35-treated mice.•Their combination with the AChE inhibitor donepezil, but not with the NMDA receptor antagonist ...memantine, shows synergy for neuroprotective effects.•The synergy involves combined action at α7 nAChR and σ1R.•Symptomatic effects are purely additive.
Drugs activating the sigma-1 (σ1) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called σ1 receptor (σ1R) agonists modulate cholinergic and glutamatergic systems in a variety of physiological responses, we addressed their putative additive/synergistic action in combination with cholinergic or glutamatergic drugs. The selective σ1 agonist PRE-084, or the non-selective σ1 drug ANAVEX2-73 was combined with the acetylcholinesterase inhibitor donepezil or the NMDA receptor antagonist memantine in the nontransgenic mouse model of AD-like memory impairments induced by intracerebroventricular injection of oligomeric Aβ25–35 peptide. Two behavioral tests, spontaneous alternation and passive avoidance response, were used in parallel and both protective and symptomatic effects were examined. After determination of the minimally active doses for each compound, the combinations were tested and the combination index (CI) calculated. Combinations between the σ1 agonists and donepezil showed a synergic protective effect, with CI<1, whereas the combinations with memantine showed an antagonist effect, with CI>1. Symptomatic effects appeared only additive for all combinations, with CI=1. A pharmacological analysis of the PRE-084+donepezil combination revealed that the synergy could be due to an inter-related mechanism involving α7 nicotinic ACh receptors and σ1R. These results demonstrated that σ1 drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatory molecular chaperone of the σ1R could eventually lead to synergistic combinations.
For some time now, the research on sigma receptors has been at a high level of maturity but, despite everything that has already been achieved, further work in this field still holds huge appeal, ...with vast possibilities for original discoveries ...
The sigma
1
receptor (σ
1
R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca
2+
exchange between the ER and mitochondria ...by interacting with inositol-1,4,5 trisphosphate receptors (IP
3
Rs). The σ
1
R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer’s disease (AD) models in vitro and in vivo. σ
1
R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ
1
R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ
1–42
peptide. σ
1
R agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), (S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro4.5dec-3-yl)-3-(1H-indol-3-yl)propan-1-one (ANAVEX3-71, AN3-71), dehydroepiandrosterone-3 sulfate (DHEA), donepezil) increased mitochondrial ROS in a σ
1
R antagonist-sensitive manner but decreased Aβ
1–42
-induced increase in ROS. σ
1
R ligands (agonists or antagonists) did not impact respiration but attenuated Aβ
1–42
-induced alteration. σ
1
R agonists (PRE-084, AN1-41, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AN2-73), AN3-71) increased complex I activity, in a Ca
2+
-dependent and σ
1
R antagonist-sensitive manner. σ
1
R ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σ
1
R-induced increase in ROS since ligands failed to affect other sources of ROS accumulation in mitochondria and homogenates, namely NADPH oxidase (NOX) and superoxide dismutase (SOD) activities. Furthermore, Aβ
1–42
significantly decreased the activity of complexes I and IV and σ
1
R agonists attenuated the Aβ
1–42
-induced complex I and IV dysfunctions. σ
1
R activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Aβ) conditions.
Flavonoids are polyphenolic natural products and have shown significant potential as disease‐modifying agents against neurodegenerative disorders like Alzheimer's disease (AD), with activities even ...in vivo. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in several phenotypic screening assays related to neurodegeneration and AD. Therefore, we have exchanged the flavonoid part of the hybrids with different flavonoids, which show higher efficacy than taxifolin or silibinin, to improve the activity of the respective hybrids. Chemical connection between the flavonoid and cinnamic acid was realized by an amide instead of a labile ester bond to improve stability towards hydrolysis. To investigate the influence of a double bond at the C‐ring of the flavonoid, the dehydro analogues of the respective hybrids were also synthesized. All compounds obtained show neuroprotection against oxytosis, ferroptosis and ATP‐depletion, respectively, in the murine hippocampal cell line HT22. Interestingly, the taxifolin and the quercetin derivatives are the most active compounds, whereby the quercetin derivate shows even more pronounced activity than the taxifolin one in all assays applied. As aimed for, no hydrolysis product was found in cellular uptake experiments after 4 h whereas different metabolites were detected. Furthermore, the quercetin‐cinnamic acid amide showed pronounced activity in an in vivo AD mouse model at a remarkably low dose of 0.3 mg/kg.
Flavonoid‐cinnamic acid amides were synthesized and evaluated in phenotypic screening assays related to neurodegeneration. The compounds prevent cell death in models of oxidative stress and energy breakdown. The introduction of an amide yielded higher stability towards hydrolysis and altering the flavonoid core structure showed that the quercetin‐cinnamic acid amide hybrid was the most potent compound, and its in vitro properties could be translated into high activity in an in vivo AD mouse model.
Wolfram syndrome (WS) is a rare neurodegenerative disease, the main pathological hallmarks of which associate with diabetes, optic atrophy, and deafness. Other symptoms may be identified in some but ...not all patients. Prognosis is poor, with death occurring around 35 years of age. To date, no treatment is available. WS was first described as a mitochondriopathy. However, the localization of the protein on the endoplasmic reticulum (ER) membrane challenged this hypothesis. ER contacts mitochondria to ensure effective Ca
transfer, lipids transfer, and apoptosis within stabilized and functionalized microdomains, termed "mitochondria-associated ER membranes" (MAMs). Two types of WS are characterized so far and Wolfram syndrome type 2 is due to mutation in CISD2, a protein mostly expressed in MAMs. The aim of the present review is to collect evidences showing that WS is indeed a mitochondriopathy, with established MAM dysfunction, and thus share commonalities with several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as metabolic diseases, such as diabetes.
Alzheimer's disease (AD) is a neurodegenerative pathology associated with aging characterized by the presence of senile plaques and neurofibrillary tangles that finally result in synaptic and ...neuronal loss. The major component of senile plaques is an amyloid-β protein (Aβ). Recently, we characterized the effects of a single intracerebroventricular (icv) injection of Aβ fragment (25-35) oligomers (oAβ(25-35)) for up to 3 weeks in rats and established a clear parallel with numerous relevant signs of AD. To clarify the long-term effects of oAβ(25-35) and its potential role in the pathogenesis of AD, we determined its physiological, behavioral, biochemical and morphological impacts 6 weeks after injection in rats. oAβ(25-35) was still present in the brain after 6 weeks. oAβ(25-35) injection did not affect general activity and temperature rhythms after 6 weeks, but decreased body weight, induced short- and long-term memory impairments, increased corticosterone plasma levels, brain oxidative (lipid peroxidation), mitochondrial (caspase-9 levels) and reticulum stress (caspase-12 levels), astroglial and microglial activation. It provoked cholinergic neuron loss and decreased brain-derived neurotrophic factor levels. It induced cell loss in the hippocampic CA subdivisions and decreased hippocampic neurogenesis. Moreover, oAβ(25-35) injection resulted in increased APP expression, Aβ(1-42) generation, and increased Tau phosphorylation. In conclusion, this in vivo study evidenced that the soluble oligomeric forms of short fragments of Aβ, endogenously identified in AD patient brains, not only provoked long-lasting pathological alterations comparable to the human disease, but may also directly contribute to the progressive increase in amyloid load and Tau pathology, involved in the AD physiopathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest ...that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3h/day for 3weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation.
Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)–mitochondrion signaling affects intramitochondrial calcium (Ca2+ ) homeostasis and cellular ...bioenergetics. ER–nucleus signaling attenuates ER stress. ER–plasma membrane signaling regulates cytosolic Ca2+ homeostasis and ER–mitochondrion–plasma membrane signaling regulates hippocampal dendritic spine formation. Here, we propose that the sigma-1 receptor (Sig-1R), an ER chaperone protein, acts as an inter-organelle signaling modulator. Sig-1Rs normally reside at the ER–mitochondrion contact called the MAM ( m itochondrion- a ssociated ER m embrane), where Sig-1Rs regulate ER–mitochondrion signaling and ER–nucleus crosstalk. When cells are stimulated by ligands or undergo prolonged stress, Sig-1Rs translocate from the MAM to the ER reticular network and plasmalemma/plasma membrane to regulate a variety of functional proteins, including ion channels, receptors and kinases. Thus, the Sig-1R serves as an inter-organelle signaling modulator locally at the MAM and remotely at the plasmalemma/plasma membrane. Many pharmacological/physiological effects of Sig-1Rs might relate to this unique action of Sig-1Rs.
Abstract Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We ...investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β25–35 peptide (Aβ25–35 ) in rat, a validated acute model of AD. Aβ25–35 induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ25–35 induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ25–35 , which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity.
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