Neurogenic Inflammation

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Introduction[edit | edit source]

Inflammation is known to be the driving factor in many diseases, including atherosclerosis, cancer, autoimmunity and chronic infections and a major contributor in age-related conditions. The classical definition of inflammation includes rubor (redness), calor (warmth), dolor (pain), and tumor (swelling), as stated by Celsus (30BC-38AD), and functio laesa (loss of function), as added by Galen (129AD-210AD). Ideally, inflammation is known to play a protective role by invading pathogens or endogenous substances such as damaged cells, and eliminates the initial cause of injury, clears the necrotic cells, and aids in tissue repair.[1] But the complexity of the molecular, immunological and physiological processes involved in the inflammatory reaction leads to the inflammatory process in various tissues and diseases, like complex regional pain syndrome, migraine, and irritable bowel, arthritis, bladder inflammation, asthma and bladder syndromes.

Neurogenic inflammation (NI) is a physiological process in which mediators are released directly from the cutaneous nerves to initiate an inflammatory reaction in response to tissue damage or a painful stimuli. In the setting of wound healing, neurogenic inflammation helps maintain tissue integrity and facilitate tissue repair.[2]

Mechanism of Injury[edit | edit source]

Host defense is important for the survival of any organism in order to prevent harm from tissue damage and infection. It involves 2 actions; an avoidance behavior to remove contact with a dangerous (noxious) environment (a neural function), and active neutralization of pathogens (an immune function). Traditionally, the immune system and the neurological system were thought to have distinct roles in dealing with infections and tissue injury; the immune system in charge of neutralizing infections, while the neurological system receives and transmits pain and feeling signals. However, recent research suggest that these two systems may actually work together as part of a unified defense mechanism, highlighting the interconnected nature of host defense and tissue repair. [2]

Tissues exposed to the external environment, such as skin, lungs, urinary, and digestive tract epithelial surfaces, are extensively innervated by high-threshold pain-producing nociceptors. The transmission of harmful external stimuli is almost instantaneous, faster than innate immune system, making it the first host defense responder. Also the action potentials in nociceptor neurons travels antidromically in reverse direction towards the periphery which is known as the axon reflex. Persistent local depolarizations, result in the fast and local release of neural mediators from both peripheral axons and terminals.

It is also known that electrical stimulation of dorsal roots induces vasodilation in the epidermis, leading to the concept of neurogenic inflammation that is separate from immune-mediated inflammation[2]. Neurogenic inflammation is initiated by activation of peripheral nervous system C-fibre neurons causing a release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), [2]. The mediators affect the vasculature along with directly attracting and activating the innate immune cells (mast cells/dendrites) and adaptive immune cells ( T lymphocytes)which triggers inflammation at the site that is different from the original stimuli. This integrated interaction between the immune and nervous systems serves as a protective mechanism in host defense and response to tissue injury, but can also contribute to pathology in allergic and autoimmune diseases.

Post Stroke Depression[edit | edit source]

Post Stroke Depression (PSD) is one of the most common mood disorders with depressive consequences in stroke patients[3]. PSD affects approximately one-third of stroke patients[4] and is a significant factor in poor recovery[5], negatively affecting the quality of life, functional ability and prognostic outcomes[5]. Studies suggests that it is also linked to an increased likelihood of stroke recurrence and death[6][7]. Improvement in functional abilities is associated with reduction of depressive symptoms; patients treated for depression show a better functional prognosis compared to untreated, depressed patients[8].

Mechanisms of inflammation: Several mechanisms correlate PSD to neurologic dysfunction[5]. It is seen that inflammation is closely linked with depression. There is evidence of the central role of neuroinfammation in development of post stroke depression[9]. Various studies show increase in secretion of proinflammatory cytokines interleukin (IL)‑1β, IL-6, IL-8, and tumor necrosis factor α (TNFα).[5].Higher serum CRP levels are linked to post-stroke cognitive impairment. Serum CRP is the most reliable stroke recovery prognostic factor.

During an ischemic injury, a series of complex neurochemical events occur that are characterised by:

  • focal cerebral hypoperfusion,
  • bioenergetic failure, excitotoxicity,
  • acidotoxicity,
  • oxidative stress,
  • microvascular injury,
  • post-ischemic inflammation,
  • blood brain barrier disruption and finally
  • death of neurons, endothelial cells, and neuroglia[5]

Inflammation resulting from stroke and depression impacts neuroplasticity, as seen by the decreased availability of brain-derived neurotrophic factor (BDNF) in synapses. A disproportionate increase in stress also causes physiological changes predisposing patients to hypertension and cardiac dysrhythmias. Individual’s emotional and social experiences triggers the activation of various components of the immune and inflammatory pathways. Cytokines act a mediator in chronic inflammatory processes linked to stroke-related complications

Factors: Various factors influence the severity and duration of PSD. [9]

  • Genetic factors: Research shows that the serotonin-transporter-linked polymorphic region 5-HTTLPR and STin2VNTR polymorphisms of the serotonin transporter gene (SERT) and hypermethylation of the 5-HTTLPR s/s genes have been associated with PSD in stroke survivors.[9][10]
  • Location of the lesion: Various observations are noticed concerning the site of lesion and PSD with some studies indicating lesions proximal to or in the frontal pole, or the limbic area to be frequently associated with PSD, whereas other studies not supporting these topological correlations. While several studies linked PSD with lesions of the medial prefrontal cortex, thalamus, amygdala, or pallidum by defining the disruption of frontal cortico‑limbic neuronal circuits, dorsolateral prefrontal and left cerebellar hemispheric localization.[9] Evidence shows that that neuronal degeneration can occur in distal areas of the brain several weeks to months post-stroke. This secondary neurodegeneration (SND) results in progressive death of neurons in distal regions of the brain that were not initially affected by the reduction in cerebral blood flow due to stroke but are anatomically closer to the site of infarction as confirmed by various imaging studies. Thalamus, hippocampus, and basal ganglia are the most commonly affected by secondary neurodegeneration.[11]
  • Physical disability: In some patients, physical disability may be a causation factor.[9] There is a link between severity of impairments/disability and PSD.[10]
  • Cognitive impairments: According to various studies, there exists a link between PSD and cognitive deficits. [10]
  • Social Support: Lack of social support is associated with PSD
  • Medical and psychiatric history: Personal history of depression and/or anxiety, diabetes was considered as risk factors for PSD.

Diagnosis: According to DSM-5, poststroke mood disorders are mood disorders due to stroke with depressive features, major depressive-like episode, or mixed-mood features. Patients must have depressed mood or loss of interest or pleasure along with at least two but less than five symptoms of major depression lasting 2 weeks or longer.[10]

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  1. ↑ Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ, Golenbock D, Gresnigt MS, Heneka MT, Hoffman HM, Hotchkiss R. A guiding map for inflammation. Nature immunology. 2017 Aug 1;18(8):826-31.
  2. ↑ 2.0 2.1 2.2 2.3 Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation – the peripheral nervous system’s role in host defense and immunopathology. Nat Neurosci. 2012;15:1063-1067.
  3. ↑ (Robinson RG and Jorge RE: Post-stroke depression: A review. Am J Psychiatry. 173:221–231. 2016.PubMed/NCBI View Article : Google Scholar).
  4. ↑ Hackett, M.L.; Pickles, K. Part I: Frequency of depression after stroke: An updated systematic review and meta-analysis of observational studies. Int. J. Stroke 2014, 9, 1017–1025
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Wijeratne T, Sales C. Understanding why post-stroke depression may be the norm rather than the exception: The anatomical and neuroinflammatory correlates of post-stroke depression. Journal of Clinical Medicine. 2021 Apr 14;10(8):1674.
  6. ↑ Wu QE, Zhou AM, Han YP, Liu YM, Yang Y, Wang XM, Shi X. Poststroke depression and risk of recurrent stroke: A meta-analysis of prospective studies. Medicine. 2019 Oct;98(42).
  7. ↑ Sibolt G, Curtze S, Melkas S, Pohjasvaara T, Kaste M, Karhunen PJ, Oksala NK, Vataja R, Erkinjuntti T. Post-stroke depression and depression-executive dysfunction syndrome are associated with recurrence of ischaemic stroke. Cerebrovascular Diseases. 2013 Dec 1;36(5-6):336-43.
  8. ↑ Paolucci S, Iosa M, Coiro P, Venturiero V, Savo A, De Angelis D and Morone G: Post-stroke depression increases disability more than 15% in ischemic stroke survivors: A case-control study. Front Neurol. 10(926)2019.PubMed/NCBI View Article : Google Scholar
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Nagy EE, Frigy A, Szász JA, Horváth E. Neuroinflammation and microglia/macrophage phenotype modulate the molecular background of post-stroke depression: A literature review. Experimental and Therapeutic Medicine. 2020 Sep 1;20(3):2510-23.
  10. ↑ 10.0 10.1 10.2 10.3 Medeiros GC, Roy D, Kontos N, Beach SR. Post-stroke depression: a 2020 updated review. General hospital psychiatry. 2020 Sep 1;66:70-80.
  11. ↑ Stuckey SM, Ong LK, Collins-Praino LE, Turner RJ. Neuroinflammation as a key driver of secondary neurodegeneration following stroke?. International Journal of Molecular Sciences. 2021 Dec 3;22(23):13101.

 

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