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Basic Hypothesis and Therapeutics Targets of Depression: a Review ISSN: 2641-1911 DOI: 10.33552/ANN.2021.10.000738 Archives in Neurology & Neuroscience Review Article Copyright © All rights are reserved by Anil Kumar Basic Hypothesis and Therapeutics Targets of Depression: A Review Monika Kadian, Hemprabha Tainguriya, Nitin Rawat, Varnika Chib, Jeslin Johnson and Anil Kumar* Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh 160014, India *Corresponding author: Dr. Anil Kumar, PhD, Professor of Pharmacology, Phar- Received Date: May 11, 2021 macology division, University Institute of Pharmaceutical Sciences, Panjab Univer- sity, Chandigarh 160014, India. Published Date: June 07, 2021 Abstract Depression is a psychological disorder marked by emotional symptoms such as melancholy, anhedonia, distress mood, loss of interest in daily life activities, feeling of worthlessness, sleep disturbances and destructive tendencies. According to WHO, more than 264 million people from all randomage groups processes are suffering during with brain depression development. thus, Depression it is become is mainlya leading due cause to neurotransmitter of disability and imbalances, infirmity worldwide. HPA disturbances, It is estimated increased that oxidative 40% of riskand nitrosativefor depression damage, is genetic impairment and the in other glucose 60% metabolism, is non-genetic and whichmitochondrial involved dysfunction, acute & chronic etc. The stress, monoamine childhood hypothesis trauma, viral is based infections on attenuation and even of monoamines such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in the brain regions (hippocampus, limbic system and frontal cortex) that can cause depression like symptoms. Depression is also marked by increased level of corticotrophin-releasing hormone (CRH) and and impaired responsiveness to glucocorticoid hormone. The present review emits about its background knowledge, various pathophysiological pathways involved and current therapy for the depression. Keywords: Depression, HPA axis, mitochondrial dysfunction, NMDA receptor, Serotonin, Glutamate Introduction glucose metabolism, and mitochondrial dysfunction, etc [3]. The Depression is one in all the two diagnostic classes that represent monoamine hypothesis is based on attenuation of monoamines common mental disorders (CMDs), the other is anxiety disorder. such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in the brain regions (hippocampus, limbic system and frontal the mood or feelings of affected persons. Depressive disorders are Both are highly widespread among the community and influence cortex) that can cause depression like symptoms. Monoaminergic characterized by dejection, loss of pleasure, guilt feelings or low neurotransmitters are metabolised by monoamine oxidase selfworth, insomnia, appetite imbalance, feelings of tiredness, and (MAO) [4,5]. Decreased antioxidant status, elevated oxidative loss of concentration. At a worldwide level, according to WHO 2020 and nitrosative stress are found in patients with depression [6]. more than 264 million people from all age group are suffering with Moreover, there is greater secretion of corticotrophin-releasing hormone (CRH) and impaired responsiveness to glucocorticoids depression, equivalent to 4.4% of the world’s population. India is [7]. The hypothalamic-pituitary-adernal (HPA) axis hyperactivity world estimate) littered with depression [1]. Depression may be home to an estimated fifty seven million people (18% of the the caused due to neurotransmitter imbalances [2], increased oxidative depressed). and nitrosative damage in brain, HPA disturbances, impairment in is present in around 50% of depressed patients (80% if severely This work is licensed under Creative Commons Attribution 4.0 License ANN.MS.ID.000738. Page 1 of 7 Archives in Neurology and Neuroscience Volume 10-Issue 3 Decreased antioxidant concentration, and raised oxidative and nitrosative stress are major marker that are present in patients the progression of chronic stress-induced depressive disorders [18]. in brain is reflective of neurotoxicity and neuronal death towards with major depression [8]. This is evidenced by reduced level of Nitric oxide (NO) is an important modulator of depression [19,20] antioxidants such as vitamin C [9] vitamin E [10,11] and coenzyme because NO production is increased in depression. Moreover, Q10 [12] in plasma and by reduced antioxidant enzyme activity In brain, No is an essential neurotransmitter that normalize such as glutathione peroxidase [13]. These paucities in antioxidant depression, behavioral, cognitive and emotional processes [21]. In defence system impaired the protection against reactive oxygen experimental animals, plasma nitrate levels have been increased species (ROS), which lead to damaged fatty acids, proteins and DNA. In depression, there is rise in the lipid peroxidation levels, physical stressors can inhibit the neurogenesis in various animal significantly under stressful condition [22]. Psycho-social and encompassing increase in malondialdehyde [14-16] and oxidative models and thus lead to decreased cell proliferation and survival damage to DNA, characterized by increased levels of 8-hydroxy-2- [23]. The types of depression are depicted in Figure 1. deoxyguanosine [17]. Furthermore, elevated oxidative stress level Figure 1: Types of depression. Pathophysiological Hypotheses of Depression Following neurotransmitters and receptor systems have been reported to be involved in pathophysiology of depression (Figure 2&3) Figure 2: The different pathological mechanisms of depression. Citation: Monika Kadian, Hemprabha Tainguriya, Nitin Rawat, Varnika Chib, Jeslin Johnson, Anil Kumar. Basic Hypothesis and Therapeutics Page 2 of 7 Targets of Depression: A Review : 10.33552/ANN.2021.10.000738. Arch Neurol & Neurosci. 10(3): 2021. ANN.MS.ID.000738. DOI Archives in Neurology and Neuroscience Volume 10-Issue 3 Figure 3: The different pathological mechanisms of depression. Role of monoaminergic system/ monoamine theory 5-HT as the foremost cause of depression, which can be altered by and mood. This terminology mainly based on the deficiency in antidepressants, which would bring back the actual functioning in functional inadequacy of adrenergic neurotransmitters such as Basic hypothesis of depression firstly described about the the affected subjects. As approved by the post-mortem examination, noradrenaline (NAdr), serotonin (5-HT) and dopamine (DA). neurochemical, genetic neuroimaging and pharmacological studies Facts for this hypothesis obtained from the animal experiments and clinical studies, which depicted that the reserpine (an regions which is known to play role in controlling emotions have antihypertensive drug), a monoamine antagonist lead to the that a purposeful insufficiency in 5-HT neuronal firing within brain systematically been related to facet of the MDD pathophysiology. reduction of pre-synaptic stores of NAdr, DA and 5-HT, was used to treat things like high blood pressure, is rarely used at the present treat the symptoms of depression. This fact more reinforced the time due to the fact that depression is a common side effect. Thus, Moreover, subsequently SSRIs solely were seem to be efficient to involvement of 5-HT within the pathological process of the illness not solely monoamine agonists decrease depression, however [26]. 5-HT is implicated in MDD, and the genesis of this disease may monoamine antagonists (Reserpine) will induce depression [24]. be linked to the dysfunctioning of 5-HT receptors [27]. It has been The enzyme (monoamine oxidase) which plays an essential role reported that 5-HT sensitivity (reduction of 5-HT/tryptophan), is in the malfunctioning and oxidation of monoamines like DA, NE more common in MDD patients [28]. Membrane transporters which and 5-HT. The monoamine oxidase A showing targeted preferred help in translocation of 5-HT across the membrane are basically action on serotonin, and its an important target for screening proteinaceous in nature and mostly targeted for the treatment of antidepressant activity of monoamine oxidase inhibitors [24]. depression. These proteins help in the regulation of serotonergic Neuronal framework of depression transmission that are also associated with MDD. Several reported literature provides the evidences of Role of hypothalamic-pituitary-adrenal (HPA) axis sys- deformities in various parts of the brain that are the main driven tem force for controlling emotion, functions and reward outcomes. Post- The response systems for stress are mainly regulated by the mortem and neuroimaging examination have depicted the changes HPA-axis. In the central nervous system when HPA-axis starts in morphology which is illustrated by reduced grey-matter volume and interstitial tissue density in the hippocampus and anterior stimulus (e.g., a traumatic episodes) from the surrounding [29]. cortex, which is the main focused region in animal analysis of stimulation, than an individual’s recognize the fearful and noxious Various researchers noted that the HPA-axis showing sensitivity depression. The decline in hippocampal operate, that is believed to towards psychological ans social stress agents, which is observed possess a repressive result on the hypothalamic-pituitary- adrenal by alteration in cortisol levels which is accompanied with the (HPA) axis, might probably be answerable for the hypercortisolemia increased risk of producing altered psychological symptoms in seen in depression [25].
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