Implication of the Kallikrein-Kinin system in neurological disorders: Quest for potential biomarkers and mechanisms

Abstract

Neurological disorders represent major health concerns in terms of comorbidity and mortality worldwide. Despite a tremendous increase in our understanding of the pathophysiological processes involved in disease progression and prevention, the accumulated knowledge so far resulted in relatively moderate translational benefits in terms of therapeutic interventions and enhanced clinical outcomes. Aiming at specific neural molecular pathways, different strategies have been geared to target the development and progression of such disorders. The kallikrein-kinin system (KKS) is among the most delineated candidate systems due to its ubiquitous roles mediating several of the pathophysiological features of these neurological disorders as well as being implicated in regulating various brain functions. Several experimental KKS models revealed that the inhibition or stimulation of the two receptors of the KKS system (B1R and B2R) can exhibit neuroprotective and/or adverse pathological outcomes. This updated review provides background details of the KKS components and their functions in different neurological disorders including temporal lobe epilepsy, traumatic brain injury, stroke, spinal cord injury, Alzheimer's disease, multiple sclerosis and glioma. Finally, this work will highlight the putative roles of the KKS components as potential neurotherapeutic targets and provide future perspectives on the possibility of translating these findings into potential clinical biomarkers in neurological disease.

Blockade of Kinin B1 receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice

“…Although still not fully elucidated the molecular mechanism triggered by decreasing of ovarian hormones on the pain process and major depression. Clinical and preclinical data suggest that the decrease of ovarian hormones induce: (I) alteration of angiotensin-converting enzyme (ACE) activity, (II) increase of oxidative stress, and (III) increase of pro-inflammatory cytokines [45][46][47], which leads to increased production of kinin and receptors activation [40,48].…”

Proteomic identification of elevated saliva kallikrein levels in the mdx-4cv mouse model of Duchenne muscular dystrophy

“…The kallikrein/kinin and bradykinin signaling axis of vasoactive peptides is involved in blood pressure regulation, tissue homeostasis and renal function. In addition, the endogenous kallikrein/kinin system was shown to be involved in various neurological diseases [27] and appears to play a protective role in dystrophic mdx muscle [28] . Building on these findings and the recent proteomic identification of greatly reduced levels of the kallikrein-1 related peptidase Klk1-b9 in mdx muscle [29] , it was of interest to study the status of kallikreins in mdx-4cv saliva specimens.…”

Hypersensitivity reactions to recombinant tissue plasminogen activator

“…Plasmin also activates the complement and kinin pathways leading to inflammatory cytokine upregulation, increased blood–mucosa and blood–brain barrier permeability and release of glutamate by glial cells. Therefore, if rtPA triggers a hypersensitivity reaction, it may be mediated by histamine (complement cascade), bradykinin (kinin pathway) or possibly both 4–6…”

“…They are rapidly overexpressed after brain infarction in mice 24 25. Once bound to receptors, bradykinin exerts a potent proinflammatory and pro-oedematous effect by increasing blood–mucosa and blood–brain barrier permeability, inflammatory cytokine upregulation, the release of glutamate by astrocytes and microglial activation4 5…”

“…Alongside histamine, rtPA-induced plasmin also triggers bradykinin overexpression4 5 (figure 1). Bradykinin may lead to blood–mucosa and blood–brain barrier leakage leading to orolingual angioedema, cerebral oedema and intracerebral haemorrhage 34.…”