Page last updated: 2024-10-24

regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of oxidative stress-induced neuron intrinsic apoptotic signaling pathway. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie]

Oxidative stress, a major contributor to neuronal dysfunction and death, triggers intricate signaling cascades that culminate in apoptosis, a programmed cell death process. The regulation of this process involves a complex interplay of signaling molecules, transcription factors, and cellular components, ultimately determining the fate of the neuron.

**1. Initial Trigger: Reactive Oxygen Species (ROS)**

* Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms. ROS, such as superoxide radicals, hydrogen peroxide, and hydroxyl radicals, can damage cellular components, including lipids, proteins, and DNA.

**2. Mitochondrial Dysfunction: A Central Player**

* Mitochondria play a critical role in cellular respiration and are particularly susceptible to oxidative stress. Excessive ROS production can disrupt mitochondrial electron transport chain function, leading to a decrease in ATP production and an increase in the generation of ROS.
* The accumulation of ROS can trigger the opening of the mitochondrial permeability transition pore (mPTP), a channel in the mitochondrial membrane that allows the release of pro-apoptotic factors, such as cytochrome c, into the cytoplasm.

**3. Caspase Cascade Activation: The Executioner of Apoptosis**

* Cytochrome c, upon release from the mitochondria, binds to apoptotic protease activating factor-1 (Apaf-1), forming the apoptosome complex.
* The apoptosome recruits and activates caspase-9, an initiator caspase, which in turn activates downstream effector caspases, such as caspase-3 and caspase-7.
* Activated caspases initiate a cascade of proteolytic events that dismantle the cell, leading to its demise.

**4. Transcription Factor Activation: Regulating Gene Expression**

* Oxidative stress can also activate transcription factors, such as p53 and NF-κB, which regulate the expression of genes involved in apoptosis and inflammation.
* p53, a tumor suppressor gene, can induce the expression of pro-apoptotic genes, while NF-κB can activate genes involved in both pro- and anti-apoptotic signaling pathways.

**5. Antioxidant Defense Mechanisms: A Balancing Act**

* The cell possesses a network of antioxidant defense mechanisms to mitigate the damaging effects of ROS. These mechanisms include enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, which convert ROS into less harmful species.
* Other antioxidant molecules, such as glutathione and vitamins E and C, also play a role in scavenging ROS.

**6. Signaling Pathway Crosstalk: A Complex Network**

* The regulation of oxidative stress-induced apoptosis is not a linear process but rather a complex network involving the interplay of multiple signaling pathways.
* The involvement of various signaling molecules, such as MAPKs, PI3K/Akt, and JNK, further adds to the complexity of this process.

**7. Neuroprotective Mechanisms: Strategies for Survival**

* The brain has developed several neuroprotective mechanisms to protect neurons from oxidative stress and apoptosis.
* These mechanisms include the induction of heat shock proteins, the activation of autophagy, and the upregulation of antioxidant genes.

**8. Implications for Neurological Diseases**

* Oxidative stress-induced apoptosis plays a significant role in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease.
* Understanding the intricate mechanisms underlying this process is crucial for developing effective therapeutic strategies to combat these debilitating disorders.'
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Proteins (1)

ProteinDefinitionTaxonomy
Poly [ADP-ribose] polymerase 1A poly [ADP-ribose] polymerase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09874]Homo sapiens (human)

Compounds (53)

CompoundDefinitionClassesRoles
niacinamidenicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group.pyridine alkaloid;
pyridinecarboxamide;
vitamin B3
anti-inflammatory agent;
antioxidant;
cofactor;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor;
EC 3.5.1.98 (histone deacetylase) inhibitor;
Escherichia coli metabolite;
geroprotector;
human urinary metabolite;
metabolite;
mouse metabolite;
neuroprotective agent;
Saccharomyces cerevisiae metabolite;
Sir2 inhibitor
1,5-dihydroxyisoquinoline1,5-dihydroxyisoquinoline: structure in first source

isoquinoline-1,5-diol : An isoquinolinol that is isoquinoline in which the hydrogens at positions 1 and 5 are replaced by hydroxy groups.
isoquinolinolEC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
3-aminobenzamidebenzamides;
substituted aniline
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
4-amino-1,8-naphthalimide4-amino-1,8-naphthalimide: inhibits ADP-ribosylation; sometimes abreviated as 4-AN;benzoisoquinoline;
dicarboximide
phenanthridonephenanthridone : A member of the class of phenanthridines that is phenanthridine with an oxo substituent at position 6. A poly(ADP-ribose) polymerase (PARP) inhibitor, it has been shown to exhibit immunosuppressive activity.

phenanthridone: coal tar derivative; structure given in first source
lactam;
phenanthridines
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor;
immunosuppressive agent;
mutagen
5-aminoisoquinolinone5-aminoisoquinolinone: structure in first sourceisoquinolines
benzamidebenzamide : An aromatic amide that consists of benzene bearing a single carboxamido substituent. The parent of the class of benzamides.benzamides
pj-34PJ34 : A member of the class of phenanthridines that is 5,6-dihydrophenanthridine substituted at positions 2 and 6 by (N,N-dimethylglycyl)amino and oxo groups, respectively. It is a potent inhibitor of poly(ADP-ribose) polymerases PARP1 and PARP2 (IC50 of 110 nM and 86 nM, respectively) and exhibits anti-cancer, cardioprotective and neuroprotective properties.phenanthridines;
secondary carboxamide;
tertiary amino compound
angiogenesis inhibitor;
anti-inflammatory agent;
antiatherosclerotic agent;
antineoplastic agent;
apoptosis inducer;
cardioprotective agent;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor;
neuroprotective agent
1-hydroxyphthalazine1-hydroxyphthalazine: RN given refers to cpd with unspecified locants; do not confuse with cpd phthalazinol RN: 56611-65-5phthalazines
chlorthenoxazinchlorthenoxazin: RN given refers to parent cpd; structurebenzoxazine
isocarbostyrilisoquinolinone : An isoquinoline containing one or more oxo groups.isoquinolines
flavoneflavone : The simplest member of the class of flavones that consists of 4H-chromen-4-one bearing a phenyl substituent at position 2.

flavone: RN given refers to unlabeled cpd; structure given in first source
flavonesmetabolite;
nematicide
2,4(1h,3h)-quinazolinedione2,4(1H,3H)-quinazolinedione: structure given in first source
4-hydroxybenzamide
naphthalimidesNaphthalimides: Compounds with three fused rings that appear like a naphthalene fused to piperidone or like a benz(de)isoquinoline-1,3-dione (not to be confused with BENZYLISOQUINOLINES which have a methyl separating the naphthyl from the benzyl rings). Members are CYTOTOXINS.
4-fluorobenzamide4-fluorobenzamide: structure in first source
5-iodo-6-amino-1,2-benzopyrone
alantolactonealantolactone : A sesquiterpene lactone that is 3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2-one bearing two methyl substituents at positions 5 and 8a as well as a methylidene substituent at position 3.

alantolactone: allergenic sesquiterpene lactone; crystalline mixture of alantolactones from group of sesquiterpenes; structure
naphthofuran;
olefinic compound;
sesquiterpene lactone
antineoplastic agent;
apoptosis inducer;
plant metabolite
4-aminobenzamidebenzamides
4-Methoxybenzamidebenzamides
3-methoxybenzamide
3',4'-dihydroxyflavone3',4'-dihydroxyflavone: inhibitors of arachidonic acid peroxidation
3,4-dihydro-5-methyl-1(2h)-isoquinolinone3,4-dihydro-5-methyl-1(2H)-isoquinolinone: structure given in first sourceisoquinolines
1-oxo-1,2,3,4-tetrahydroisoquinoline1-oxo-1,2,3,4-tetrahydroisoquinoline: structure given in first source
cyclo(alanylalanyl)
N-[4-[[[4-(4-methoxyphenyl)-4-oxanyl]methylamino]-oxomethyl]phenyl]-2-furancarboxamidearomatic amide;
furans
ha 1100HA 1100: intracellular calcium antagonist
apigeninChamomile: Common name for several daisy-like plants (MATRICARIA; TRIPLEUROSPERMUM; ANTHEMIS; CHAMAEMELUM) native to Europe and Western Asia, now naturalized in the United States and Australia.trihydroxyflavoneantineoplastic agent;
metabolite
luteolin3'-hydroxyflavonoid;
tetrahydroxyflavone
angiogenesis inhibitor;
anti-inflammatory agent;
antineoplastic agent;
apoptosis inducer;
c-Jun N-terminal kinase inhibitor;
EC 2.3.1.85 (fatty acid synthase) inhibitor;
immunomodulator;
nephroprotective agent;
plant metabolite;
radical scavenger;
vascular endothelial growth factor receptor antagonist
amentoflavonebiflavonoid;
hydroxyflavone;
ring assembly
angiogenesis inhibitor;
antiviral agent;
cathepsin B inhibitor;
P450 inhibitor;
plant metabolite
3',4',7-trihydroxyflavone3',4',7-trihydroxyflavone: from the Sudanese medicinal plant Albizia zygia; structure in first sourceflavones
adenosine diphosphate (hydroxymethyl)pyrrolidinedioldihydroxypyrrolidine;
purine ribonucleoside 5'-diphosphate
ag 14361benzimidazoles
gpi 6150
rucaparibAG14447: Poly(ADP-ribose) polymerase inhibitor; structure in first sourceazepinoindole;
caprolactams;
organofluorine compound;
secondary amino compound
antineoplastic agent;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2h)-isoquinolinone
veliparibbenzimidazolesEC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
olaparibcyclopropanes;
monofluorobenzenes;
N-acylpiperazine;
phthalazines
antineoplastic agent;
apoptosis inducer;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
niraparib2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide : A member of the class of indazoles that is 2H-indazole substituted by 4-(piperidin-3-yl)phenyl and aminocarbonyl groups at positions 2 and 7, respectively. It is a potent PARP1 inhibitor with IC50 of 3.2 nM.benzenes;
indazoles;
piperidines;
primary carboxamide
antineoplastic agent;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
niraparibniraparib : A 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide that has S-configuration. It is a potent inhibitor of PARP1 and PARP2 (IC50 of 3.8 and 2.1 nM, respectively) and approved as a first-line maintenance treatment for women with advanced ovarian cancer after responding to platinum-based chemotherapy.

niraparib: structure in first source
2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamideantineoplastic agent;
apoptosis inducer;
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor;
radiosensitizing agent
cep 26401pyridazines;
ring assembly
iwr-1 endoIWR-1-endo : A dicarboximide having an endo bridged phthalimide structure, substituted at nitrogen by a 4-(quinolin-8-ylcarbamoyl)benzoyl group.benzamides;
bridged compound;
dicarboximide;
quinolines
axin stabilizer;
Wnt signalling inhibitor
nms-p118NMS-P118: a PARP-1 inhibitor; structure in first source
g007-lkG007-LK: potent and specific small-molecule tankyrase inhibitor; structure in first source
nu 1025NU 1064: structure in first sourcephenols;
quinazolines
EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor
2-methyl-4(3h)-quinazolinone2-methyl-4(3H)-quinazolinone: from Bacillus cereus; structure given in first source
4-hydroxyquinazoline4-oxo-3,4-dihydroquinazoline: structure in first sourcequinazolines
1,4-Dihydrothieno[3,2-d]pyrimidin-4-oneorganic heterobicyclic compound;
organonitrogen heterocyclic compound;
organosulfur heterocyclic compound
xav939XAV939 : A thiopyranopyrimidine in which a 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine skeleton is substituted at C-4 by a hydroxy group and at C-2 by a para-(trifluoromethyl)phenyl group.

XAV939: selectively inhibits beta-catenin-mediated transcription; structure in first source
(trifluoromethyl)benzenes;
thiopyranopyrimidine
tankyrase inhibitor
2-(4-methoxyphenyl)-1H-quinazolin-4-onequinazolines
bmn 673talazoparib: inhibits both PARP1 and PARP2; structure in first source
me0328ME0328: inhibits ARTD3; structure in first source
nvp-tnks656