Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies
Abstract
:1. Major Depressive Disorder and Excessive Aggression
2. Animal Models of Excessive Aggression
Animal Model | Strains | Core Characteristics | References |
---|---|---|---|
Genetic Models | |||
Knock-out dopamine D2 receptor | D2R−/− mice | Elevated aggression in males, reduced hypothalamic orexin precursor expression, increased serum prolactin levels | [21,48] |
Knock-out α-isoform of the oestrogen receptor | ERα−/− mice | Elevated aggression in males, compromised neuroplasticity | [23,24] |
Knock-out arginine vasopressin V1b receptor | V1bR−/− mice | Elevated aggression in males, compromised neuroplasticity, decreased neurogenesis | [49] |
Knock-out dopamine β-hydroxylase | DBH−/− mice | Elevated aggression in males, compromised neuroplasticity, decreased insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2) signalling | [26,48] |
Knock-out tryptophan hydroxylase 2 | Tph2−/− male mice | Elevated aggression in males, decreased 5-HT level, compromised neuroplasticity | [27,28] |
Knock-out 5-HT1B receptor | 5-HT1B−/− mice | Elevated aggression in males, deficient neuroplasticity | [29] |
Knock-out dopamine transporter | DAT−/− mice | Elevated aggression in males, deficient synaptic plasticity | [30] |
Knock-out nitric oxide synthase | NOS−/− mice | Elevated aggression in males, compromised neuroplasticity, antioxidant system disbalance | [31] |
Knock-out MAOA | MAOA−/− mice | Elevated aggression in males, deficient synaptic plasticity and pruning, disbalance of brain monoamine levels | [32] |
Bred for short attack latency (SAL) | SAL mice | Elevated aggression, low brain 5-HT level, reduced 5-HT reuptake transporter activity | [33,34] |
Turku Aggressive mice | Turku Aggressive mice | Elevated aggression in males | [35] |
North Carolina 900 mice | NC900 mice | Elevated aggression in males, reduced GABA-ergic neurotransmission | [36] |
North Carolina 100 mice | NC100 mice | Elevated aggression in males, lower dopamine concentrations | [36] |
Wistar rats with low anxiety-like behaviour (LAB) | LAB rats | Elevated aggression in males, compromised neuroplasticity | [37,38] |
Environment Stress Models | |||
Social isolation | CD1, C57BL/6J mice | Excessive aggressive behaviour in males, alterations in the function of the HPA axis | [41,42,43,44] |
Maternal separation | C57BL/6J mice | Rats: increased intermale aggression at 14–16 weeks of age, lowered maternal aggression. Mice: females are more aggressive towards male intruders; males are less aggressive towards male intruders | [45,46] |
Chronic mild stress | BALB/C, CD1, C57BL/6J mice | Increased offensive and aggressive behaviours in males; GSK3-β overexpression; microglial activation, reduced neuroplasticity | [18,50,51,52,53,54,55] |
Rat exposure | C57BL/6 mice | Increased aggressive behaviour in males, aberrant neurogenesis, reduced neuroplasticity; oxidative stress | [52,56] |
Social defeat | C57BL/6 mice | Excessive aggression in dominant males, microglial activation, reduced neuroplasticity and synaptic pruning, deficient neurogenesis, GSK3-β overexpression, oxidative stress | [57,58,59,60,61] |
Ultrasound stress | BALB/C, CD1, C57BL/6J mice; Wistar, Sprague-Dawley rats | Increased aggressive behaviours in males; microglial activation, reduced neuroplasticity, GSK3-β overexpression, oxidative stress | [62,63,64,65,66,67] |
Maternal Models | |||
Stimuli from pups | BALB/C, CD1, C57BL/6J mice; Wistar, Sprague-Dawley rats; Syrian hamsters; | Increased aggressive behaviours in females, deficient neuroplasticity and reduced neurogenesis | [68,69,70,71] |
Gene × Environment Interaction Models | |||
Deficiency of tryptophane hydroxylase and 5-day predation stress | Tph2+/− male mice | Increased aggressive behaviours in males; reduced brain serotonin content, reduced expression of 5-HT6 receptor, GSK3-β overexpression | [72] |
Tph2+/− female mice | Increased aggressive behaviours in females; reduced brain serotonin content, GSK3-β and myelin basic protein overexpression; deficient neuroplasticity, downregulation of synaptophysin | [73] |
3. Neuroanatomical Basis of Aggression in Humans and Rodents in the Context of Depressive Disorder
4. Neuroinflammatory Mechanisms of Depression and Excessive Aggression
5. Oxidative Stress Markers, Insulin Receptor Signalling and Excessive Aggression
6. Role of Disrupted Myelination and Connectivity in Excessive Aggression and Impulsivity Associated with Depressive Syndrome
7. Challenges in the Management of Excessive Aggression
8. New Strategies in Pharmacological Management of Pathological Aggression
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug Class | Drug Examples | Strains | Core Targets | References |
---|---|---|---|---|
Benzodiazepine | Adinazolam Diazepam | Sprague-Dawley rats | Facilitating GABAergic transmission, decreasing neuronal excitability | [223,224] |
TCA | Amitriptyline Desipramine Imipramine | Sprague-Dawley rats, Wistar rats, C57BL/6J mice | Blocking of serotonin transporter SERT and norepinephrine transporter NET, inhibition of sodium channels, reversed lipid peroxidation | [225,226,227,228] |
SSRI | Citalopram Escitalopram Fluoxetine | Sprague-Dawley rats, Wistar rats | Inhibition of serotonin reuptake, increased norepinephrine transmission, upregulation of BDNF, anti-inflammatory effects | [229,230] |
MAOI | Moclobemide | Sprague-Dawley rats | Inhibition of monoamine oxidase activity, deamination of serotonin and norepinephrine | [231] |
NMDA antagonist | Ketamine MK-801 | Wistar rats | Inhibition of ionotropic NMDA receptors, anti-inflammatory effects | [232,233,234] |
SNRI | Duloxetine | Sprague-Dawley rats | Inhibition of serotonin and norepinephrine reuptake, antioxidant activity | [235] |
Typical antipsychotic | Haloperidol | Wistar rats | Blocking of dopamine receptor type 2 | [236,237] |
Essential vitamins and their synthetic derivates | Thiamine Benfotiamine Dibenzoylthiamine Vitamin E | BALB/C, CD1, C57BL/6J mice | Antioxidant activity, increased neuroplasticity, overexpression of BDNF, anti-inflammatory effects, downregulation of GSK3-β, increased glutathione content | [56,62,66,238,239,240] |
Insulin receptor sensitizers | Rosiglitazone Pioglitazone | BALB/C, CD1, C57BL/6J mice | Decreased neuronal damage, anti-inflammatory effects, increased mitochondrial biogenesis | [187,241,242] |
Treatment | Model | Effects on Aggression | Other Effects | References |
---|---|---|---|---|
Ascorbic acid Beta carotene Vitamin E N-acetyl cysteine | Isolation, or L-DOPA, male Swiss albino mice | ↓ | Increased levels of GSH, SOD, CAT in brain | [261] |
Lithium chloride | Shock-induced, Sprague-Dawley rats; shock induced plus d-AMP or scopolamine, Walter Reed rats; isolation, AB mice; resident-intruder, TO mice | ↓ | — | [269] |
Shock-induced, CD-1, C57BL/6J and FVB/N mice | ↓ | Increased brain norepinephrine turnover | [270] | |
Thiamine Benfothiamine Dibenzoylthiamine | Ultrasound-induced, BALB/c mice | ↓ | Anxiolytic, anti-depressant, reduced inflammation and oxidative stress | [56,66,238,240,271] |
Dicholine succinate | C57BL/6N mice; Western diet, C57BL/6 mice; chronic stress, CD-1 mice; defeat stress, C57BL/6J mice | ↓ (pilot data) | Anxiolytic, anti-depressant, prevention of Tlr4 upregulation in brain | [188,272,273] |
Rosiglitazone | Chronic social defeat, C57BL/6J mice | Not assessed | Anxiolytic, anti-depressant | [274] |
Chlorogenic acid extract from Prunus domestica or Beta vulgaris | Swiss albino mice, alone or with restraint stress | Not assessed | Anxiolytic, anti-depressant, reduced ROS production by immune cells in vitro, increased GSH level and decreased MDA in brain tissue | [275,276] |
Ulva sp. extract | Wistar rats | Not assessed | Anti-depressant | [277] |
Extract of blackberry chamomile, garlic, cloves, and elderberry | Resiquimod- or LPS-induced inflammation, CD-1 mice | Not assessed | Anxiolytic, anti-depressant. Reduced expression of SAA2, ACE2, CXCL1, CXCL10, Il-1β, Il-6 in spleen and liver. Normalized counts of neutrophiles, monocytes, eosinophiles. | [278] |
Standardized herbal cocktail (see [63] for composition) | Ultrasound stress, BALB/c and C57BL/6 mice | ↓ (pilot data) | Anti-depressant. Decreased brain MDA and protein-carbonyl, decreased brain expression of IL-1β and IL-6 | [63] |
Standardized herbal cocktail (see [62] for composition) | Ultrasound stress, BALB/c mice | ↓ | Anti-depressant. Decreased brain expression of Il-1β, Il-6, TNF, GSK-3β. Increased expression of Ki67, decreased brain MDA | [62] |
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Gorlova, A.; Svirin, E.; Pavlov, D.; Cespuglio, R.; Proshin, A.; Schroeter, C.A.; Lesch, K.-P.; Strekalova, T. Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies. Int. J. Mol. Sci. 2023, 24, 915. https://doi.org/10.3390/ijms24020915
Gorlova A, Svirin E, Pavlov D, Cespuglio R, Proshin A, Schroeter CA, Lesch K-P, Strekalova T. Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies. International Journal of Molecular Sciences. 2023; 24(2):915. https://doi.org/10.3390/ijms24020915
Chicago/Turabian StyleGorlova, Anna, Evgeniy Svirin, Dmitrii Pavlov, Raymond Cespuglio, Andrey Proshin, Careen A. Schroeter, Klaus-Peter Lesch, and Tatyana Strekalova. 2023. "Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies" International Journal of Molecular Sciences 24, no. 2: 915. https://doi.org/10.3390/ijms24020915