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Background and Purpose: A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex.As a reference, we applied nimodipine, a vasodilator dihydropyridine and wellknown calcium channel antagonist.Experimental Approach: Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine).In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia.Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry.Key Results: LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect.Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. Conclusions and implications:In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.Abbreviations: 2VO, permanent, bilateral occlusion of the common carotid arteries ("two-vessel occlusion"); CBF, cerebral blood flow; DC, direct current; EFP, evoked field potential; eNOS, endothelial NOS; Hsp, heat shock protein; LDF, laser Doppler flowmetry; LFP, local field potential; MABP, mean arterial BP; rSD, recurrent spreading depolarization; SD, spreading depolarization; SD1, the first spreading depolarization in a train of events

Selective elimination of microglia from the brain was shown to dysregulate neuronal Ca2+ signaling and to reduce the incidence of spreading depolarization (SD) during cerebral ischemia. However, the mechanisms through which microglia interfere with SD remained unexplored. Here, we identify microglia as essential modulators of the induction and evolution of SD in the physiologically intact brain in vivo. Confocal- and super-resolution microscopy revealed that a series of SDs induced rapid morphological changes in microglia, facilitated microglial process recruitment to neurons and increased the density of P2Y12 receptors (P2Y12R) on recruited microglial processes. In line with this, depolarization and hyperpolarization during SD were microglia- and P2Y12R-dependent. An absence of microglia was associated with altered potassium uptake after SD and increased the number of c-fos-positive neurons, independently of P2Y12R. Thus, the presence of microglia is likely to be essential to maintain the electrical elicitation threshold and to support the full evolution of SD, conceivably by interfering with the extracellular potassium homeostasis of the brain through sustaining [K+]e re-uptake mechanisms.

Secondary injury following acute brain insults significantly contributes to poorer neurological outcome. The spontaneous, recurrent occurrence of spreading depolarization events (SD) has been recognized as a potent secondary injury mechanism in subarachnoid hemorrhage, malignant ischemic stroke and traumatic brain injury. In addition, SD is the underlying mechanism of the aura symptoms of migraineurs. The susceptibility of the nervous tissue to SD is subject to the metabolic status of the tissue, the ionic composition of the extracellular space, and the functional status of ion pumps, voltage-gated and other cation channels, glutamate receptors and excitatory amino acid transporters. All these mechanisms tune the excitability of the nervous tissue. Aging has also been found to alter SD susceptibility, which appears to be highest at young adulthood, and decline over the aging process. The lower susceptibility of the cerebral gray matter to SD in the old brain may be caused by the age-related impairment of mechanisms implicated in ion translocations between the intra-and extracellular compartments, glutamate signaling and surplus potassium and glutamate clearance. Even though the aging nervous tissue is thus less able to sustain SD, the consequences of SD recurrence in the old brain have proven to be graver, possibly leading to accelerated lesion maturation. Taken that recurrent SDs may pose an increased burden in the aging injured brain, the benefit of therapeutic approaches to restrict SD generation and propagation may be particularly relevant for elderly patients.

L-Kynurenine (L-KYN) is a central metabolite of tryptophan degradation through the kynurenine pathway (KP). The systemic administration of L-KYN sulfate (L-KYNs) leads to a rapid elevation of the neuroactive KP metabolite kynurenic acid (KYNA). An elevated level of KYNA may have multiple effects on the synaptic transmission, resulting in complex behavioral changes, such as hypoactivity or spatial working memory deficits. These results emerged from studies that focused on rats, after low-dose L-KYNs treatment. However, in several studies neuroprotection was achieved through the administration of high-dose L-KYNs. In the present study, our aim was to investigate whether the systemic administration of a high dose of L-KYNs (300 mg/bwkg; i.p.) would produce alterations in behavioral tasks (open field or object recognition) in C57Bl/6j mice. To evaluate the changes in neuronal activity after L-KYNs treatment, in a separate group of animals we estimated c-Fos expression levels in the corresponding subcortical brain areas. The L-KYNs treatment did not affect the general ambulatory activity of C57Bl/6j mice, whereas it altered their moving patterns, elevating the movement velocity and resting time. Additionally, it seemed to increase anxiety-like behavior, as peripheral zone preference of the open field arena emerged and the rearing activity was attenuated. The treatment also completely abolished the formation of object recognition memory and resulted in decreases in the number of c-Fos-immunopositive-cells in the dorsal part of the striatum and in the CA1 pyramidal cell layer of the hippocampus. We conclude that a single exposure to L-KYNs leads to behavioral disturbances, which might be related to the altered basal c-Fos protein expression in C57Bl/6j mice.

The neuroactive properties and neuroprotective potential of endogenous L: -kynurenine, kynurenic acid (KYNA) and its derivatives are well established. KYNA acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. Unfortunately, KYNA is barely able to cross the blood-brain barrier. Accordingly, the development and synthesis of KYNA analogs which can readily cross the BBB have been at the focus of research interest with the aim of neuroprotection. Earlier we reported a new KYNA-amide crosses the BBB and proved neuroprotective in several experiments. In the present study, we investigated the locomotor activity, working memory performance, and also the long-lasting, consolidated reference memory of animals treated intraperitoneally (i.p.) with the novel analog. The effects of the novel analog on the spatial orientation and learning ability of rats were assessed in the Morris water maze (MWM) paradigm. The effects on locomotor activity of mice was assessed in the open field (OF) paradigm, and those on the spatial orientation and learning ability of mice were investigated in the radial arm maze (RAM) paradigm. It emerged that there is a dose of this KYNA-amide which is neuroprotective, but does not worsen the cognitive function of the brain. This result is significant in that a putative neuroprotectant without adverse cognitive side-effects is of great benefit.

Since brain ischemia is one of the leading causes of adult disability and death, neuroprotection of the ischemic brain is of particular importance. Acute neuroprotective strategies usually have the aim of suppressing glutamate excitotoxicity and an excessive N-methyl-d-aspartate (NMDA) receptor function. Clinically tolerated antagonists should antagonize an excessive NMDA receptor function without compromising the normal synaptic function. Kynurenic acid (KYNA) an endogenous metabolite of the tryptophan metabolism, may be an attractive neuroprotectant in this regard. The manipulation of brain KYNA levels was earlier found to effectively enhance the histopathological outcome of experimental ischemic/hypoxic states. The present investigation of the neuroprotective capacity of L-kynurenine sulfate (L-KYNs) administered systemically after reperfusion in a novel distal middle cerebral artery occlusion (dMCAO) model of focal ischemia/reperfusion revealed that in contrast with earlier results, treatment with L-KYNs worsened the histopathological outcome of dMCAO. This contradictory result indicates that post-ischemic treatment with L-KYNs may be harmful.