Activation of α7-nAChRs Promotes the Clearance of α-Synuclein and Protects Against Apoptotic Cell Death Induced by Exogenous α-Synuclein Fibrils

Misfolding and abnormal aggregation of α-synuclein (αSyn) have been shown to increase the risk of developing Parkinson's disease (PD). Finding some way to reduce the aggregation of αSyn is particularly important for the treatment of PD. The main route in prion-like αSyn spreading is the cholinergic innervated vagus nervous system and central cholinergic neurons. Since the degenerative changes and death of cholinergic neurons also run through the pathological process of PD, we hypothesize an involvement of the cholinergic system in αSyn aggregation. The α7 nicotinic acetylcholine receptors (α7-nAChRs) are one of the most abundant nAChRs in the mammalian brain. Using nicotine and a selective α7-nAChRs agonist PNU-282987, we found a protective effect of α7-nAChRs on the cell damage induced by αSyn-PFF (preformed fibrils) through inhibiting apoptotic cell death. We further discovered an additive effect of α7-nAChRs on the clearance of αSyn in normal and αSyn stably transduced SH-SY5Y cells. Moreover, using α7-nAChRs knockout mice, we noticed that α7-nAChRs deficiency increased the deposition of αSyn and aggravated the loss of dopaminergic neurons in a chronic MPTP mouse model of PD. Our findings for the first time indicated that α7-nAChRs activation exhibited a neuroprotective effect on αSyn pathology and aggregation by promoting the clearance of αSyn.

Download Full-text

Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

Cell Death and Disease ◽

10.1038/s41419-020-03328-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tong Zhao ◽

Tihua Zheng ◽

Huining Yu ◽

Bo Hua Hu ◽

Bing Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Lysosomal Enzymes ◽

Apoptotic Cell ◽

Cell Damage ◽

Treatment Strategies ◽

Explant Culture ◽

Apoptotic Cell Death ◽

Lysosomal Dysfunction ◽

Autophagic Degradation

AbstractMacroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

Download Full-text

Abstract WP62: Enhanced Neuroprotection of Normobaric Oxygenation with Ethanol Conferred by Apoptosis Reduction in Acute Ischemic Stroke

Stroke ◽

10.1161/str.44.suppl_1.awp62 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Sweena Parmar ◽

Xiaokun Geng ◽

Changya Peng ◽

Murali Guthikonda ◽

Yuchuan Ding

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Caspase 3 ◽

Apoptotic Cell ◽

Neuroprotective Effect ◽

Apoptotic Cell Death ◽

Ethanol Administration ◽

Sprague Dawley ◽

Apoptotic Proteins

Objectives: Normobaric oxygenation (NBO) has been shown to provide neuroprotection in vivo and in vitro . Yet, a recent Phase 2 clinical trial investigating NBO therapy in acute ischemic stroke was terminated due to questionable therapeutic benefit. NBO therapy alone may be insufficient to produce improved outcomes. In our recent study, we demonstrated a strong neuroprotective effect of ethanol at a dose of 1.5 g/kg (equivalent to the human legal driving limit). In this study, we sought to identify whether low-dose ethanol administration enhances the neuroprotection offered by NBO and whether combined administration of NBO with ethanol is associated with reduced apoptosis. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. Ischemic animals received either an intraperitoneal injection of 1.0 g/kg ethanol, 2 h of 100% NBO, or both ethanol and NBO. The Cell Death Detection ELISA Assay (Roche) was performed to determine apoptotic cell death at 24 h after reperfusion. Levels of pro-apoptotic (Caspase-3, Bcl-2-associated X-BAX, and Apoptosis-Inducing Factor-AIF) and anti-apoptotic proteins (Bcl-2 and Bcl-xL) were determined by Western blot analysis at 3 and 24 h after reperfusion. Results: As expected, untreated ischemic rats had the highest apoptotic cell death. Combined NBO/ethanol therapy decreased cell death by 48%, as compared to 29% with ethanol and 22% with NBO. Similarly, combined NBO/ethanol therapy promoted the greatest expression of anti-apoptotic factors and the lowest expression of pro-apoptotic proteins at 3 h after reperfusion. This effect was maintained at 24 h and even more pronounced for AIF and Caspase-3. Conclusions: Given singularly, NBO and ethanol improved the degree of cell death, decreased the expression of pro-apoptotic proteins, and increased the expression of anti-apoptotic proteins. Yet, when administered together, their effects largely compounded. These results suggest a synergistic neuroprotection offered by NBO with ethanol, which may be attributed at least in part to their shared role in modulating neuronal apoptosis.

Download Full-text

Distribution of Cholinergic Neurons in the Mammalian Brain with Special Reference to their Relationship with Neuronal Nicotinic Acetylcholine Receptors

Handbook of Experimental Pharmacology - Neuronal Nicotinic Receptors ◽

10.1007/978-3-642-57079-7_2 ◽

2000 ◽

pp. 13-30 ◽

Cited By ~ 12

Author(s):

M. Zoli

Keyword(s):

Special Reference ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Cholinergic Neurons ◽

Mammalian Brain ◽

Neuronal Nicotinic Acetylcholine Receptors ◽

Nicotinic Acetylcholine

Download Full-text

Role of α7- and α4β2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712001046 ◽

2013 ◽

Vol 16 (5) ◽

pp. 1105-1113 ◽

Cited By ~ 15

Author(s):

Karem H. Alzoubi ◽

Marisa Srivareerat ◽

Trinh T. Tran ◽

Karim A. Alkadhi

Keyword(s):

Chronic Stress ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Short Term Memory ◽

Neuroprotective Effect ◽

Stress Conditions ◽

Nicotine Treatment ◽

Memory Tests ◽

Α7 Nachrs

Abstract We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 µg/side.d and 41 µg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.

Download Full-text

Nerve growth factor prevents apoptotic cell death in injured central cholinergic neurons

The Journal of Comparative Neurology ◽

10.1002/cne.903590405 ◽

1995 ◽

Vol 359 (4) ◽

pp. 573-585 ◽

Cited By ~ 39

Author(s):

Barbara J. Wilcox ◽

Michael D. Applegate ◽

Carlos Portera-Cailliau ◽

Vassilis E. Koliatsos

Keyword(s):

Cell Death ◽

Nerve Growth Factor ◽

Growth Factor ◽

Apoptotic Cell ◽

Cholinergic Neurons ◽

Apoptotic Cell Death ◽

Nerve Growth

Download Full-text

Ontogenesis of nicotinic acetylcholine receptors and presynaptic cholinergic neurons in mammalian brain

Life Sciences ◽

10.1016/0024-3205(86)90057-3 ◽

1986 ◽

Vol 38 (7) ◽

pp. 637-644 ◽

Cited By ~ 35

Author(s):

Shizuo Yamada ◽

Yoshiyuki Kagawa ◽

Mitsutaka Isogai ◽

Noriyasu Takayanagi ◽

Eiichi Hayashi

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Cholinergic Neurons ◽

Mammalian Brain ◽

Nicotinic Acetylcholine

Download Full-text

The Neuroprotective Effect of GPR4 Inhibition through Attenuation of Caspase Mediated Apoptotic Cell Death in MPTP Induced Mouse Model of Parkinson’s Disease

10.20944/preprints202104.0223.v1 ◽

2021 ◽

Author(s):

Md. Ezazul Haque ◽

Shofiul Azam ◽

Mahbuba Akther ◽

Duk-Yeon Cho ◽

Kim In Su ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Neuroprotective Effect ◽

Neuronal Loss ◽

Apoptotic Cell Death ◽

Substantia Nigra Pars Compacta ◽

Motor Deficit ◽

Motor Deficits ◽

Mice Model ◽

Dopaminergic Neuronal Loss

GPR4, a member of proton activated GPCRs group. Previously we have reported that GPR4 is constitutively active at physiological pH and knockout of GPR4 has shown to protect dopaminergic neuronal cells from caspase-dependent mitochondrial apoptotic cell death. In this study we have investigated the role of GPR4 in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated mice model of Parkinson’s disease. Subchronic administration of MPTP in mice produces oxidative stress induced apoptotic cell death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and motor deficits. Treatment with NE52-QQ57, a selective antagonist of GPR4 reduced dopaminergic neuronal loss MPTP-intoxicated C57BL6/J mice and improved motor deficit and memory impairment. Co-treatment with NE52-QQ57 significantly decreases the protein level of proapoptotic marker (Bax), and increases the antiapoptotic marker (Bcl-2) in the SNpc and striatum tissue collected from the brain of MPTP inflicted mice. Further, MPTP induced activation of caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP) was significantly decreased in the SNpc and striatum tissue of NE52-QQ57 cotreated mice. Further mice receiving both MPTP and NE52-QQ57 mice showed significantly higher TH positive cells in the SNpc and striatum than MPTP treated mice alone. Moreover, NE52-QQ57 cotreatment improved the motor activity in the rotarod test and pole test and also improved spatial memory in Y maze test. Our findings suggest GPR4 as a potential therapeutic target for PD whereas the activation GPR4 is involved in the caspase mediated apoptotic cell death in SNpc and striatum of MPTP-intoxicated mice.

Download Full-text

Neuroprotective Effect of Resveratrol Against Methamphetamine-Induced Dopaminergic Apoptotic Cell Death in a Cell Culture Model of Neurotoxicity

Current Neuropharmacology ◽

10.2174/157015911795017353 ◽

2011 ◽

Vol 9 (1) ◽

pp. 49-53 ◽

Cited By ~ 19

Author(s):

Kavin Kanthasamy ◽

Richard Gordon ◽

Huajun Jin ◽

Vellareddy Anantharam ◽

Syed Ali ◽

...

Keyword(s):

Cell Culture ◽

Cell Death ◽

Apoptotic Cell ◽

Neuroprotective Effect ◽

Apoptotic Cell Death ◽

Cell Culture Model ◽

Culture Model ◽

A Cell

Download Full-text

Abstract 142: Enhanced Neuroprotection by Synergistically Induced Hypothermia with Pharmacological and Physical Approach in Experimental Stroke

Stroke ◽

10.1161/str.48.suppl_1.142 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Kaiyin Liu ◽

Jun Zhang ◽

Yuexia Duan ◽

Di Wu ◽

Xiaokun Geng ◽

...

Keyword(s):

Cell Death ◽

Combination Therapy ◽

Transient Receptor Potential ◽

Apoptotic Cell ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Apoptotic Cell Death ◽

Experimental Stroke ◽

High Dose ◽

Transient Receptor Potential Vanilloid

Background and Purpose: This study combined Transient Receptor Potential Vanilloid channel 1 (TRPV1) receptor agonist, dihydrocapsaicin (DHC), with physical hypothermia (PH) (ice pad) to achieve faster cooling to enhance its neuroprotective effects, thus potentially avoiding side effects brought on by monotherapies of high dose DHC and physical hypothermia. Methods: Middle cerebral artery (MCA) occlusion (2 h) was achieved using an intraluminal filament. Rats (n=8) were randomized to 7 groups: sham surgery, stroke only, PH, low DHC (0.5 mg/kg), low DHC/active rewarming (AR), high DHC (1.5 mg/kg) or combination (low DHC plus PH). The treatments were maintained for 3 h at the onset of reperfusion, which was 24 h. Rate to target hypothermia (31 °C) onset was measured. Extent of brain injury was determined by infarct volume, neurological deficit, and apoptotic cell death. Expressions of pro- and anti-apoptotic proteins were evaluated through Western blotting. Metabolic changes and oxidative injury were determined by ATP and ROS productions. Results: Combination had 28.6% faster cooling than PH, 350% faster than low DHC group and 200% faster than high DHC group. Combination had 63.2% reduction in infarct volume and low DHC had 25.9% reduction in infarct volume compared to stroke only. High DHC, DHC (AR) and PH and did not induce significant neuroprotection. Combination therapy significantly decreased apoptotic cell death by 48.5%, as compared to 24.9% with low DHC, in association with significantly increased anti-apoptotic and reduced pro-apoptotic protein expression. Combination therapy largely increased ATP levels by 42.9%, as compared to 25% increase with low DHC. Only combination therapy and PH had significant reductions in ROS at 6 and 24 h post-reperfusion. Neurological testing showed that combination therapy had the best outcomes at 24 h of reperfusion. Discussion: Combination of DHC and PH enhanced the neuroprotective effect produced by each alone. This synergistic protection is associated with faster cooling and more dramatic reduction in apoptotic cell death and more favorable cellular metabolism. The combination therapy is promising in clinical settings for its non-invasive, quick and effective outcomes.

Download Full-text