We investigated whether inhibition of nitric oxide (NO) biosynthesis with N-ω-nitro-l-arginine (NNA), a competitive inhibitor of NO synthase (NOS), would modify the volume of the focal ischemic infarction produced by occlusion of the middle cerebral artery (MCA) in spontaneously hypertensive rats. NNA was infused for 1 h (2.4 mg/kg/h) immediately following occlusion of the MCA. NNA increased lesion volume 24 h later by 32% over controls (150.8 ± 16.6 to 199.2 ± 17.4 mm³; p < 0.001, n = 6). This effect was antagonized by co-infusion of l- but not d-arginine. The antihypertensive rilmenidine (0.75 mg/kg) reduced the lesion by 27% (p < 0.05, n = 4). Changes in lesion size were confined to the penumbra. NNA increased arterial pressure (AP) (118 ± 8.9 to 149 ± 16.0 mm Hg; p < 0.01, n = 3) but did not change regional CBF. However, elevation of AP did not change the lesion volume or distribution. We conclude that inhibition of the constitutive form of NOS in vivo increases the volume of focal ischemic infarction as a consequence of reduced NO biosynthesis. The absence of NO availability may extend lesion formation by inhibition of reactive hyperemia, platelet disaggregation, and/or release of neuroprotective neuromodulators in the penumbra, which may counteract and override any of its neurotoxic actions.

Background and Purpose— This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review— The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Conclusions— Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.

Trigeminocardiac reflex (TCR) is a brainstem reflex that manifests as sudden onset of hemodynamic perturbation in blood pressure (MABP) and heart rate (HR), as apnea and as gastric hypermotility during stimulation of any branches of the trigeminal nerve. The molecular and clinical knowledge about the TCR is in a constant growth since 1999, what implies a current need of a review about its definition in this changing context. Relevant literature was identified through searching in PubMed (MEDLINE) and Google scholar database for the terms TCR, oculocardiac reflex, diving reflex, vasovagale response. The definition of the TCR varies in clinical as well as in research studies. The main difference applies the required change of MABP and sometimes also HR, which most varies between 10% and 20%. Due to this definition problem, we defined, related to actual literature, 2 major (plausibility, reversibility) and 2 minor criteria (repetition, prevention) for a more proper identification of the TCR in a clinical or research setting. Latest research implies that there is a need for a more extended classification with 2 additional subgroups, considering also the diving reflex and the brainstem reflex. In this review, we highlighted criteria for proper definition and classification of the TCR in the light of increased knowledge and present a thinking model to overcome this complexity. Further we separately discussed the role of HR and MABP and their variation in this context. As another subtopic we gave attention to is the chronic TCR; a variant that is rarely seen in clinical medicine.

The trigeminocardiac reflex (TCR) is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, the TCR has been reported in all the surgical procedures in which a structure innervated by the trigeminal nerve is involved. Although, there is an abundant literature with reports of incidences and risk factors of the TCR; the physiological significance and function of this brainstem reflex has not yet been fully elucidated. In addition, there are complexities within the TCR that requires examination and clarification. There is also a growing need to discuss its cellular mechanism and functional consequences. Therefore, the current review provides an updated examination of the TCR with a particular focus on the mechanisms and diverse nature of the TCR.

Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune-brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region-specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches.