Can Pharmacological Inhibitors and Antibodies Against m CRP Suppress Interactions with Platelets and Leukocytes-Dampening Inflammation after Stroke

RS Baradie1, AM Algohary2,3*, Esam S Al-Malki4, Yasser HS Babair5, Abdulrahman M Alsulaiman6, Suliman A Alsagaby7 and Slevin M8 1Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Saudi Arabia 2Chemistry Department, Sciences college zulfi, Saudi Arabia 3Pharmaceutical Chemistry Department, National Organization for Drug Control and Research (NODCAR), Egypt 4Medical Laboratory Department, College of Applied Medical Sciences, Saudi Arabia 5Director of Northern Armed Forces Hospital’s Ministry of Defense Medical Services, Saudi Arabia 6Consultant in Molecular & Medical Virology. PSMMC Riyadh, Saudi Arabia 7Assistant professor, Department Medical Laboratory Sciences, College of Applied Medical Sciences, Saudi Arabia 8Cell Pathology School of Life Sciences Manchester Metropolitan University Manchester, UK


Introduction
Alzheimer's disease (AD) is the greatest public formula of dementia disorder [1]. The modern therapeutic means existing to physicians serve mainly to improve patient symptoms and are incapable to stop the progressive decline in cognitive function that is the mark of AD [1]. It is hoped that new generations of agents will be able to slow or even halt the progression of dementia. However, it is likely that any significant therapeutic advance will rely upon an improvement in our current understanding of the pathophysiology of AD, enabling novel treatment approaches to be developed. We have formerly revealed that (m CRP) was deposited in the brain extracellular matrix (ECM) of patients after critical stroke [3].
Furthermore, Cerebrovascular disease, neurovascular dysfunction and cerebral blood flow abnormalities are now recognized as critical influences in the pathophysiological development of AD, damaged, blocked or in patent vessels having a severe effect on the function of local neurovascular units (with approximately 80% of AD brains at post-mortem shown to have significant vascular abnormalities). Damage to the deep penetrating vessels within the brain such as following lacunar stroke, ischaemic stroke or head trauma, may lower the threshold for development of vascular and other (mixed) dementia, particularly in younger patients [4,5].
Also, in the last investigation we determine localization within the brain and indicators of previous stroke or vascular disruption in nonhuman samples [6]. Chronic neuroinflammation is strongly associated with later development of cognitive decline and dementia/Alzheimer's disease Selles MC et al. [7] and in addition, acute events such as ischaemic stroke, traumatic brain injury, and intracerebral haemorrhage as well as smaller vascular insults associated with for example lacunar stroke predispose individuals significantly to neurodegenerative complications Rensma et al. [8], Vinters et al. [9].
C-reactive protein has long been known to represent a useful marker of both acute and chronic inflammation Slevin et al. [6] however only in recent years has it, and particularly its monomeric form (m CRP-monomeric C-reactive protein) been shown to be biologically active within the brain and strongly associated with neuroinflammation and degeneration if not directly a causative factor in development of dementia Luan and Yao [10]. The involvement of m CRP in angiogenesis and vascular abnormalities Boras E et al. [11] prompted us here to examine small cohort of human brain samples from individuals after death who had clinical and pathological evidence of the existence of stroke and/or dementia. We analyzed specifically the localization of m CRP within vascular regions of the brain. Prior studies have attempted to shown that m CRP is deposited in significant quantities within the brain parenchyma after stroke, and we have recently identified a possible role of this protein in supporting neurodegeneration and aberrant vascular development. Recent clinical trials for AD have focused on attempts to remove pathological substrates e.g. amyloid-p, tau and neurofibrillary tangles (NFTs). So far, they have been unsuccessful.
Here we can fix two hypothesize First one is vascular disruption and concomitant releasing of m CRP within the human brain tissue could increase on-going neurological damage via stimulation of neuroinflammation and from direct consequences of its action on both neuronal and vascular cells. Second, there are no pharmacological agents with regulative approval for use in the treatment of vascular dementia and novel approaches are desperately needed.

Methods
Alzheimer's tissue (post mortem) from 10 patients and was obtained from the Brain Bank in Bristol (UK). Tissue sections were obtained from blocks of the cerebral cortex, specifically, from the frontal lobe, parietal lobe and occipital lobe. Details are shown in Table 1  ; CAA= cerebral amyloid angiopathy; TBI=traumatic brain injury. Results: We showed that monomeric-C-reactive protein deposition was highest in those regions affected by stroke or vascular disruption, and that within those same areas, there was more interaction and co-localization between major classical proteins of neurodegeneration (β-amyloid and tau).

Results
Of the 10 patient samples examined, 7 showed significant macroscopically visible and specifically m CRP positive regions that were associated with vascular structures and abnormal looking brain tissue parenchymal morphology. The major highlights were as follows: A

Conclusion
For the first time, here we have provided evidence of m CRPbuild-up within small and medium sized micro-vessels within the brain tissue localized to stroke. We capture the release into brain parenchymal tissue of m CRP and a concomitant activation of regional and focal blood vessels where they are exposed to this protein. This work provides further evidence to support a prominent role for m CRP in induction of inflammation and neurodegenerative capability after stroke and brain damage. Also, we introduce pharmacological agents with characteristic a preventative, protective and treatment for AD.