KYNA Derivatives with Modified Skeleton; Hydroxyquinolines with Potential Neuroprotective Effect

Kynurenic acid (KYNA) is an endogenous neuroprotective agent of increasing importance. Several derivatives have already been synthesized, bearing an abundance of functional groups attached to the main skeleton in different positions. Several of these compounds have already been tested in biological evaluations, with several of them targeting the same receptors and biological effects as KYNA. However, these modified compounds build upon the unmodified KYNA skeleton leaving a possible route for the synthesis of new, potentially neuroprotective derivatives with heteroatom-containing ring systems. The aim of this review is to summarize the syntheses of KYNA derivatives with altered skeletons and to pinpoint an appealing transformation for future medicinal lead molecules.

L-Serine, an Endogenous Amino Acid, Is a Potential Neuroprotective Agent for Neurological Disease and Injury

Central nervous system (CNS) lesions are major causes of human death and disability worldwide, and they cause different extents of motor and sensory dysfunction in patients. Thus, it is crucial to develop new effective neuroprotective drugs and approaches targeted to the heterogeneous nature of CNS injury and disease. L-serine is an indispensable neurotrophic factor and a precursor for neurotransmitters. Although L-serine is a native amino acid supplement, its metabolic products have been shown to be essential not only for cell proliferation but also for neuronal development and specific functions in the brain. Growing evidence has suggested that L-serine regulates the release of several cytokines in the brain under some neuropathological conditions to recover cognitive function, improve cerebral blood flow, inhibit inflammation, promote remyelination and exert other neuroprotective effects on neurological injury. L-serine has also been used to treat epilepsy, schizophrenia, psychosis, and Alzheimer’s Disease as well as other neurological diseases. Furthermore, the dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine generally support the safety of L-serine. The high significance of this review lies in its emphasis on the therapeutic potential of using L-serine as a general treatment for numerous CNS diseases and injuries. Because L-serine performs a broad spectrum of functions, it may be clinically used as an effective neuroprotective agent.

Timely and Appropriate Administration of Inhaled Argon Provides Better Outcomes for tMCAO Mice: a Controlled, Randomized and Double-blind Animal Study

Background: Inhaled argon (iAr) has shown promising therapeutic efficacy for acute ischemic stroke (AIS) and exhibited impressive advantages over other inert gases as a neuroprotective agent. However, the optimal dose, duration and time point of iAr for AIS are unknown. Here, we explored variable iAr schedules and evaluated the neuroprotective effects of acute iAr administration on lesion volume, brain edema, and neurological function in a mouse model of cerebral ischemic/reperfusion (I/R) injury.Methods: Adult ICR mice were randomly subjected to sham, moderate (1.5 h) or severe (3 h) transient middle cerebral artery occlusion (tMCAO). One hour after tMCAO, the mice were randomized to variable iAr protocols or air (iCtr). General and focal deficit scores were assessed during double-blind treatment. Infarct volume, overall recovery and brain edema were analyzed 24 h after cerebral I/R injury.Results: Compared with those in the tMCAO only group, lesion volume (p<0.001) and neurologic outcome (general, p<0.001; focal, p<0.001) were significantly improved in the iAr group, which was assigned to argon inhalation 1 h after ischemia (before the onset of reperfusion). Short-term argon treatment (1 h or 3 h) showed significantly better outcomes with regard to infarct volume (p<0.01) compared to argon inhalation for 24 h. The concentration of argon inhalation was confirmed to be a key factor in improving the focal neurological outcome relative to that in the tMCAO group, and higher concentrations showed better effects. In addition, even though ischemia research has shown an increase in cerebral damage proportional to ischemia time, argon administration showed significant neuroprotective efficacy on infarct volume (p<0.001), neurological deficits (general, p<0.001; focal, p<0.001), weight recovery (p<0.001), and edema (p<0.001) in general, particularly in moderate stroke.Conclusions: Timely argon inhalation before the onset of reperfusion showed optimal neurological outcomes and minimal infarct volumes. Moreover, an appropriate duration of argon administration was important for better neuroprotective efficacy. These findings may provide vital guidance for using argon as a neuroprotective agent and moving to clinical trials in acute ischemic stroke.

DEFINING OUTCOME IN ACUTE STROKE PATIENTS USING BARTHEL INDEX AND MODIFIED RANKIN SCALE TREATED WITH NEUROPROTECTIVE AGENTS

Objective: The present study was carried out to describe outcome in acute stroke patients by means of Barthel index (BI) and modified Rankin scale (mRS) treated with neuroprotective agents. Methods: One hundred acute stroke patients were divided into two groups. Group I patients were treated with citicoline as neuroprotective agent and Group II patients were treated with cerebroprotein hydrolysate as neuroprotective agent. BI and mRS were applied at 1st, 3rd, 6th and 12th week respectively. Results: The mean BI at 1st week in Group I was 35.3 and in Group II was 36.2, at 3rd week was 50.5 in Group I and 50.1 in Group II, at 6th week was 61.4 in Group I and 59.8 in Group II and at 12th week was 65.8 in Group I and 64.2 in Group II. The difference was non-significant (p>0.05). The mean mRS at 1st week in Group I was 4.5 and in Group II was 4.2, at 3rd week was 3.6 in Group I and 3.9 in Group II, at 6th week was 3.1 in Group I and 3.6 in Group II and at 12th week was 2.5 in Group I and 2.1 in Group II. The difference was non-significant (p>0.05). Conclusion: A correlation between BI and mRS from baseline to end of 12 weeks within each group was highly significant.