Page 56 - AN-3-2

Advanced Neurology Inflammation in diabetic stroke: Pathogenesis

also upregulates the expression of cyclooxygenase-2 humoral (T helper 2, Th2) response, driven by cytokine
(COX-2), which can elicit free radical generation within 3 h shift, in particularly diminished interferon gamma
of ischemia. Excess free radical results in the formation of (IFN-γ) and increased IL-10 levels. This shift is associated
57
peroxynitrite (a powerful, toxic ROS), which contributes with a reduction in lymphocyte counts and contributes to
to the eventual infarction of the penumbra. Animal the increased susceptibility to post-stroke infection. 66,67
58
studies showed that during ischemia, hyperglycemia was Although these mechanisms increase the risk of infection,
associated with higher levels of extracellular glutamate, they reduce the risk of autoreactive immune response to
leading to higher intracellular calcium, oxidative stress, brain antigens after ischemic brain damage. 53,68
and worse neuronal damage. 59
In diabetic individuals, the host’s immune response
Activated PKC in diabetes causes damage to the is disrupted, rendering them vulnerable to infections in
tight junction proteins in vascular endothelium and general. The TLR/IL-1R domain plays an important
69
overproduction of vascular endothelial growth factor, role in pathogen recognition. The expression of TLR
70
resulting in damage. The increased BBB permeability has been shown to be lower in diabetic patients with poor
60
enhances the inflammatory response following ischemic glycemic control and diabetic complications, but not in
injury. Hyperglycemia is associated with the overexpression those with good diabetic control. In vitro studies have
71
of MMP, especially MMP-9, which worsens cerebral demonstrated that peripheral blood mononuclear cells
49
edema following ischemic stroke. isolated from individuals with type 2 diabetes secreted
In summary, diabetes causes chronic systemic lesser cytokines, e.g., IL-1β, IL-6, and TNF-α, 72,73 resulting
inflammation, oxidative stress, and vascular damage, which in reduced immune responses against invading pathogens.
exacerbate oxidative stress and inflammatory responses A study has demonstrated that macrophages isolated from
during ischemic stroke, further worsening ischemic brain db/db mice, a type 2 diabetes animal model, exhibited
74
damage. Nevertheless, the evolving process of ischemia in significantly reduced phagocytosis and adhesion capacity.
a diabetic brain remains largely unclear. Furthermore, chronic hyperglycemia is associated with
defects in complement receptors on monocytes, resulting
6. Post-stroke infection in impaired phagocytosis. After ischemic stroke, the
75
enhanced immunosuppression state in individuals with
Bacterial infections, particularly urinary tract infections
and pneumonia, are common complications after stroke. diabetes renders them more susceptible to post-stroke
Stroke-associated pneumonia occurs in about 10% infection.
of patients, resulting in increased mortality and poor 7. Post-stroke long-term sequelae
functional outcome in survivors. It has been estimated
61
that infection contributes up to ~30% of overall stroke Post-stroke fatigue, depression, and dementia are
mortality within 1 year. In addition to increased infection the common stroke complications. Although the
62
risk due to sequelae of stroke, e.g., dysphagia and immobility, mechanisms are not well understood, they may be linked
stroke-induced suppression of peripheral immunity also to inflammation. Post-stroke fatigue occurs in up to 70%
st
76
contributes to the increased risk of infection. of stroke survivors in the 1 year, and about 40% of the
patients would experience persistent fatigue 2 years after
Within minutes after stroke onset, ischemia- stroke. 77,78 A meta-analysis showed that about 30% of
induced DAMPs are released into circulation, activating stroke survivors suffer from post-stroke depression, which
peripheral immune cells to express and release pro- is an independent predictor of the severity of functional
inflammatory cytokines. In the acute stroke phase, stress impairment. 79
causes overactivation of sympathetic nervous system and
hypothalamic pituitary adrenal axis causes the mobilization The exact pathophysiology of post-stroke fatigue
of more leukocytes from the spleen and bone marrow. and depression is currently unknown. Of the proposed
63
Following the early activation, which can be as early as mechanisms, post-stroke fatigue and depression may be
12 h after stroke onset, is a systemic immunodepression proinflammatory cytokine-induced sickness behavior. 80,81
state. There is a significant reduction of lymphocyte After stroke, peripheral immune cells infiltrate into
counts due to apoptotic death of the immune cells, the injured brain and secret pro-inflammatory or anti-
resulting in the loss of peripheral and splenic lymphocyte inflammatory cytokines. The disturbed balance between
64
subpopulation, and a suppression of lymphoid lineage the pro- and anti-inflammatory cytokines promotes
proliferative capacity. 53,65 Furthermore, after stroke, there chronic inflammation. 82,83 Brain inflammation alters the
is a shift of the T cell response from pro-inflammatory secretion of orexin, a neuropeptide regulating arousal
and cellular (T helper 1, Th1) to anti-inflammatory and and wakefulness in the hypothalamus, resulting in post-

Volume 3 Issue 2 (2024) 6 doi: 10.36922/an.1683