Insights into the neuropathology of cerebral ischemia and its mechanisms

Cerebral ischemia is a result of insufficient blood flow to the brain. It leads to limited supply of oxygen and other nutrients to meet metabolic demands. These phenomena lead to brain damage. There are two types of cerebral ischemia: focal and global ischemia. This condition has significant impact on patient's health and health care system requirements. Animal models such as transient occlusion of the middle cerebral artery and permanent occlusion of extracranial vessels have been established to mimic the conditions of the respective type of cerebral ischemia and to further understand pathophysiological mechanisms of these ischemic conditions. It is important to understand the pathophysiology of cerebral ischemia in order to identify therapeutic strategies for prevention and treatment. Here, we review the neuropathologies that are caused by cerebral ischemia and discuss the mechanisms that occur in cerebral ischemia such as reduction of cerebral blood flow, hippocampal damage, white matter lesions, neuronal cell death, cholinergic dysfunction, excitotoxicity, calcium overload, cytotoxic oedema, a decline in adenosine triphosphate (ATP), malfunctioning of Na+/K+-ATPase, and the blood-brain barrier breakdown. Altogether, the information provided can be used to guide therapeutic strategies for cerebral ischemia

Studies Of Clitoria Ternatea Linn. Root Extract On Behavioural Effects And In Vivo Hippocampal Synaptic Plasticity In A Rat Model Of Chronic Cerebral Hypoperfusion

Clitoria ternatea Linn. (CT) is a native plant in tropical countries like Malaysia. The root part of the plant has been studied extensively for its pharmacological activities. However, its contribution towards learning and memory enhancement together with in vivo synaptic plasticity in a chronic cerebral hypoperfusion (CCH) rat model has yet to be explored. For quality control purposes, taraxerol content (0.15% ± 0.01) in the methanolic extract of CT root was determined using validated gas chromatography-mass spectrometry (GC-MS) analytical method. In the present study, the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery method was employed to develop CCH model in rats. The acute and chronic (28 days) treatment of CT root extract at doses of 200 and 300 mg/kg, p.o. resulted in a significant enhancement in memory retention of the passive avoidance task. Effects of CT root extract were further assessed in the Morris water maze task. The results demonstrate that CT root extract (200 and 300 mg/kg, p.o.) treatment restored spatial learning and reference memory impairments induced by CCH. Chronic treatment of CT root extract (200 and 300 mg/kg, p.o.) was also found to diminish CCH-induced neuronal damage in the CA1 region of the hippocampus. An increased acetylcholinesterase (AChE) activity in the frontal cortex and hippocampus of the PBOCCA rats was significantly inhibited by the CT root extract at a high dose (300 mg/kg, p.o.). In synaptic plasticity study, CT root extract (200 and 300 mg/kg, p.o.) restored the CCH-induced in vivo hippocampal long-term potentiation (LTP) suppression at the Schaffer collateral CA3-CA1 synapse. These results indicate that CT root extract may affect learning and memory functions in PBOCCA rats via LTP facilitation. CT root extract (300 mg/kg, p.o.) did not show any improvement on spatial memory and hippocampal LTP in scopolamine (muscarinic receptor antagonist; 1.0 mg/kg, i.p.) pre-treated PBOCCA rats. In toxicity study, repeated doses of CT root extract (100, 200 and 300 mg/kg, p.o.) were found to be safe in PBOCCA rats after 28 days treatment. In conclusion, the methanolic extract of CT root extract restored the learning and memory deficits and in vivo synaptic plasticity impairment in a CCH rat model, thus supporting the therapeutic potential of CT root extract in the treatment of vascular dementia (VaD)

The NLRP3 inflammasome in age-related cerebral small vessel disease manifestations: untying the innate immune response connection

In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1β has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its’ complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets

The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection

In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1β has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its’ complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets

Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU—a crossroad of the immune–vascular–nervous system—which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets