The IQ-1S JNK (c-Jun N-Terminal Kinase) Inhibitor Suppresses Premature Aging of OXYS Rat Brain

Abstract—According to the Alzheimer’s Disease International (ADI) international organization about 50 million people in the world suffer from Alzheimer’s disease (AD). However, there are no effective methods for preventing or slowing the progression of AD. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway is discussed below as an alternative way to prevent the development of AD and other neurodegenerative diseases. In the present study, we evaluated the ability of a recently synthesized selective JNK3 inhibitor, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), to suppress neurodegenerative processes in OXYS rats at an early stage of development of AD at the ages of 4.5 to 6 months. Treatment with IQ-1S (50 mg/kg intragastrically) led to the suppression of the development of neurodegenerative processes in the cerebral cortex of OXYS rats: an increase in the proportion of unchanged neurons, a decrease in the proportion of neurons with signs of destruction and irreversible damage, and a normalization of the glioneuronal index, which was facilitated by a decrease in the severity of hyperviscosity syndrome blood in OXYS rats. The use of the IQ-1S JNK3 inhibitor may be a promising strategy for the prevention of early neurodegenerative disorders and, possibly, the treatment of AD.


INTRODUCTION
Age is a major risk factor for Alzheimer's disease (AD), which is becoming the most common cause of senile dementia. According to the international organization Alzheimer's Disease International (ADI), about 50 million people in the world suffer from AD and, according to forecasts, this number will double every 20 years [1]. In this regard, the development of ways to prevent AD has acquired particular relevance: according to the forecast, the creation of a method to delay the onset of the disease by 5 years by 2025 could reduce the number of people suffering from it by 50% in 2050 [2]. However, there are no effective methods for preventing and slowing the progression of AD, despite significant investments in their development. This is largely due to the fact that the strategy for creating drugs for the treatment of AD over the past 30 years has been directed to amyloid pathology as a central event in the pathogenesis of the disease. However, a significant expansion of ideas about the most common (>95% of cases) sporadic form of AD as a disease of a multifactorial nature has shown that the optimal approach to its treatment can be therapy that affects the systemic mechanisms of aging that underlie all related diseases. The evolutionarily conserved signaling pathway of the N-terminal c-Jun kinase (JNK) is considered as one of the potential targets for such actions [3]. JNK is a member of the mitogen-activated protein kinase (MAPK) family, as represented by three isoforms: JNK1, JNK2, and JNK3. JNKs phosphorylate and induce many transcription factors associated with apoptosis [3]. Unlike JNK1 and JNK2, JNK3 is mainly expressed in the brain, JNK3 phosphorylates the amyloid precursor protein APP and promotes its conversion to amyloid beta. JNK3 also directly phosphorylates the tau protein, regulating the formation of neurofibrillary tangles [4][5][6]. Previously, JNK3 activation in the brain of patients with familial AD was reported and its level correlated with cognitive decline in patients [7]. Currently, there is an active search for JNK3 inhibitors, many of which have already confirmed their effectiveness in various models of the early (hereditary) form of AD [8,9]. In the present study, we evaluated the neuroprotective effects of a new selective JNK inhibitor, the sodium salt of 11Hindeno [1,2-b]quinoxalin-11-one oxime (IQ-1S), which, as was found by in silico and in vitro experiments, has an increased affinity for JNK3 [10][11][12]. The study was performed on OXYS rats, which are a model of premature aging, one of the manifestations of which is accelerated brain aging, accompanied by the spontaneous development of all key signs of AD. Their sequence: mitochondrial dysfunction, hyperphosphorylation of tau protein, synaptic failure, destructive changes in neurons, behavioral disorders, and cognitive decline in the early stages and their progression against the background of an increase in the level of the amyloid precursor protein APP, increased accumulation of amyloid beta and the formation of amyloid plaques in the brain, corresponds to modern ideas about the pathogenesis of the sporadic form of AD [13]. The absence of mutations in the APP, Psen1, and Psen2 genes that are characteristic of the early form of the disease allows us to consider OXYS rats as a unique model of the sporadic form of AD [14]. Already at a young age, these animals exhibit phenomena of cerebrovascular dysfunction [15] and impaired rheological properties of blood [16], with the latter leading to a decrease in the efficiency of oxygen transport; brain tissue hypoxia, as is known, contributes to an accelerated decrease in cognitive functions and the development of AD [17]. Recently, we have shown that IQ-1S is able to inhibit the development of signs of age-related macular degeneration in OXYS rats, which also is a manifestation of premature aging in these animals [18]. The aim of this study was to evaluate the ability of IQ-1S to influence the development of neurodegenerative processes in the cerebral cortex, the state of cerebral vessels, and the rheological properties of blood at the early stages of developing signs of AD in OXYS rats.

Animals.
The work was performed on male Wistar and OXYS rats, which were obtained from the Center for Genetic Resources of Laboratory Animals of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, in accordance with the Guidelines of the European Convention for the Protection of Vertebrate Animals ("Directive 2010/63/EU of the European Parliament and Council European Union for the Protection of Animals used for Scientific Purposes"). Rats were kept in groups of five in 57 × 36 × 20-cm cages at a temperature of 22 ± 2°C under a fixed lighting regime (12 h light/12 h dark) with free access to water and food, that is, a standard pelleted diet for laboratory animals (Chara, ZAO Assortment Agro, Russia). To assess the effects of IQ-1S, 4-month-old OXYS rats were randomly assigned to two groups of ten animals. For 45 days (from the age of 4.5 to 6 months), OXYS rats of the experimental group were intragastrically injected with IQ-1S at a dose of 50 mg/kg as a suspension in 2 mL of 1% starch mucilage. OXYS rat control group received starch mucilage. An additional control consisted of ten Wistar rats, which were also injected daily with starch mucilage. The animal study was approved by the bioethics commission of the Siberian State Medical University (protocol No. 4008/4/06/2022 of June 20, 2022). Every effort has been made to minimize the number of animals used and their discomfort. Euthanasia was performed by CO 2 inhalation.
IQ-1S. The sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1S) (series M314) was synthesized as described previously [10] at the Department of Biotechnology and Organic Chemistry of the Tomsk Polytechnic University, Tomsk, Russia. The chemical structure of IQ-1S was confirmed by mass spectrometry and nuclear magnetic resonance; the purity of the substance was 99.9%. To prepare the suspension, a weighed portion of IQ-1S powder, corresponding to the appropriate dose for the animal, was aseptically triturated with a pestle with 20 μL of Tween 80; 2 mL of 1% starch mucilage was added to create a suspension.
Histological examination. For histological examination, the brains of experimental animals were fixed in 10% neutral formaldehyde in 0.1 mol/L phosphate buffer (pH 7.4) and embedded in paraffin according to the standard procedure [20], serial frontal sections were made (thickness from 4 to 5 μm), stained with toluidine blue according to the Nissl method, and the sensorimotor area of the cerebral cortex (the Fpa and Fpp fields) was isolated using a stereotaxic atlas of the brain of an adult rat [21] and examined using a microscope (Axiostar Plus, Carl Zeiss, Germany). Morphometric parameters were measured by quantitative image analysis performed with Axiovision software (Zeiss, Thornwood, NY). The evaluation was performed by examining five sections of the brain of each animal at a magnification of 10 × 100 using a frame of 900 μm 2 . The specific area of vessels (open and with stasis, sludge, or thrombosis) was measured. We also separately counted the number of neurons with central and total chromatolysis, hyperchromic neurons without signs of shrinking, and hyperchromic shrank neurons, as well as perineuronal gliocytes with nuclear pyknosis and perikaryon edema per 200 corresponding cells of layers II, IV, and V of the cortex. The number density of neuronal nuclei and perineuronal gliocytes was calculated in an ocular frame of 900 μm 2 , which were then recalculated to an area of 1 mm 2 of the section.
Electron microscopy. Samples of the sensorimotor area of the cerebral cortex of control and experimental OXYS and Wistar rats (n = 5 per group) were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.2) for 1 h, washed with 0.1 M sodium cacodylate buffer, and postfixed in 1% osmium tetroxide in the same buffer for 1 h. The samples were then washed with water and incubated in 1% aqueous uranyl acetate in the dark at RT for 1 h. The samples were then dehydrated using a graduated series of ethanol and acetone mixtures and embedded with a mixture of epon-araldite resins. First, semithin sections 1-μm thick were made on an ultratome and stained with toluidine blue, then ultrathin sections were made. Ultrathin sections were stained with uranyl acetate and lead citrate and then examined under a transmission electron microscope (JEM 100 SX; Jeol, Tokyo, Japan) at the Interdepartmental Joint Center for Microscopic Analysis of Biological Objects of the Institute of Cytology and Genetics of the Russian Academy of Sciences. On electron micrographs of the sensorimotor area of the cerebral cortex (45 photos per group of animals), all organelles located in these areas were stained using Adobe Photoshop. For each photograph, the specific total area of each type of organelle located in the electron-transparent areas of neurons was determined.

Hemorheological indices.
To assess hemorheological parameters, blood samples were taken from rats anesthetized with diethyl ether from the common carotid artery. The blood was stabilized with a 3.8% solution of sodium citrate in a ratio of 9 : 1. The viscosity of whole blood was measured on a rotary Brookfield DV-II+Pro viscometer with a "cone/plane" system at a temperature of 36°С in the range of shear rates from 15 to 450 s -1 , plasma viscosity at a shear rate of 450 s -1 . The hematocrit was determined by centrifugation in glass capillaries (an RS-6 centrifuge, 2000 rpm, and a centrifugation time of 15 min) and expressed as a percentage. The plasma fibrinogen concentration was assessed by the Claus thrombus formation method using a Fibrinogen-test reagent kit for determining the fibrinogen concentration on a Cormay KG-4 hemocoagulometer. The deformability of erythrocytes was studied on a RheoScan-AnD 300 analyzer in the shear stress range of 7-20 Pa. The tissue oxygen delivery index was calculated as the ratio of whole blood viscosity to the hematocrit [22].

Statistical analysis.
Statistical analysis was carried out using the Statistica 10 software package (Statsoft, United States) using the methods of variation statistics. The normality of the sample distribution was determined using the Shapiro-Wilk test. To assess the significance of differences when comparing mean values, nonparametric Kruskal-Wallis and Mann-Whitney tests were used. Differences were considered statistically significant at p < 0.05. Experimental data are presented in the text as mean ± standard error of the mean (M ± SEM).

IQ-1S attenuates degenerative changes in the cerebral cortex of OXYS rats.
As shown by the present study, in the sensorimotor area of the cerebral cortex of control OXYS rats at the age of 6 months, signs of neurodegeneration were quite pronounced in all layers: edema of the perikarya of neurons, glia, blood vessels, microcirculatory disorders, condensation of chromatin with the development of hyperchromatosis of nuclei with and without shrinking, chromatolysis of neurons of varying severity were detected. All these changes were visible both in overview images and at high magnification (Fig. 1).
Quantification revealed an increase in all the studied layers of the cerebral cortex of OXYS rats in the proportion of neurons altered according to the dark type, that is, with the development of hyperchromatosis of nuclei and cytoplasm, and in the light type with the dissolution of the chromatophilic substance and the development of chromatolysis. This is evidenced by a significant increase in the percentage of hyperchromic neurons with shrinking of the nucleus and cytoplasm in OXYS rats compared with Wistar rats, indicating their irreversible damage, and hyperchromic neurons without shrinking, whose appearance is associated either with an increase or decrease in their functional activity [23], and neurons with total and focal chromatolysis. Pyramidal neurons of layers II and V of the cortex of OXYS rats are more prone to dark-type changes, while sensitive neurons of layer IV are more likely to undergo chromatolysis; it is in this layer that the largest percentage of neurons with total chromatolysis was found, which also indicates irreversible damage to neurons (Table 1). At the ultrastructural level, destructive changes in neurons were accompanied by destruction of granular ER cisterns, accumulation of degradation products of membrane structures in cells in the form of deposition of lipofuscin granules, mitochondria with destruction of cristae, and the appearance of electron-dense content in the matrix (Fig. 2).
Calculation of the specific area of organelles in the cytoplasm of neurons in layer IV of the cerebral cortex of the studied animals showed that in OXYS rats of the control group compared to Wistar rats, the specific area of granular ER was reduced by 2.3 times and mitochondria, by 1.9 times; whereas the specific area of lysosomes and vacuoles was increased by 10 and 4.6 times, respectively (p < 0.05; Table 2).
Glial cells are actively involved in both the processes of life support and death of neurons. All studied layers of the cerebral cortex of OXYS rats showed signs of glial activation, which was indicated by an increase in the glioneuronal index, the ratio of glial cells to neurons (p < 0.05; Table 1). This was mainly due to an increase in the numerical density of glia, since there were no significant differences in the density of neurons in the cortex of OXYS and Wistar rats. Along with NEUROCHEMICAL  an increase in glial density, the percentage of destructively altered gliocytes increases in the cerebral cortex of OXYS rats (p < 0.05; Table 1). The pathological changes we detected in the cerebral cortex of OXYS rats developed against the background of significant disturbances in the cerebral vessels. Along with open functioning vessels with a small number of blood cells in the lumen, the cerebral cortex of OXYS rats contained capillaries with signs of partial occlusion, indicating blood flow disorders with aggregation of blood cells, stasis, and thrombosis of small vessels (Fig. 3). As a result, the specific area of open functioning vessels in control OXYS rats was 3 times lower than in Wistar rats (p < 0.001; Fig. 3).
The course administration of IQ-1S significantly improved the state of microcirculation in the cerebral cortex of animals, as evidenced by doubling of the specific area of open functioning vessels and a decrease in the specific area of vessels with signs of partial occlusion by 2.3 times compared to those found in control OXYS rats (Fig. 3d). It can be assumed that an increase in the preservation of neurons in the brain of animals was associated with the effect of IQ-1S on microcirculation. IQ-1S significantly improved the overall picture of the sensorimotor cortex in OXYS rats (Figs. 1c, 1f). In OXYS rats treated with IQ-1S, the proportion of neurons with signs of destructive changes decreased in all the studied layers of the cerebral cortex; however, only the percentage of neurons with focal chromatolysis reached the values characteristic of Wistar rats ( Table 1). The study of the ultrastructure of neurons showed that taking IQ-1S largely prevented the destruction of granular ER and mitochondria; degenerative changes in the latter were observed much less frequently. Compared with the control group, in the experimental group of OXYS rats, there was a significant increase in the specific area of granular ER and a decrease in the specific area of lysosomes; however, they did not reach the values found in Wistar rats. The proportion of the area occupied by mitochondria and vacuoles in neurons was not significantly affected by IQ-1S ( Table 2).
The course of administration of IQ-1S significantly reduced destructive changes in glial cells in the cerebral cortex of OXYS rats and normalized the glioneuronal index (Table 1). We quantitatively evaluated only perineuronal gliocytes that are in close contact with neurons. Qualitatively, all types of glial cells were assessed using electron microscopy. At the same time, in the cerebral cortex of control OXYS rats,  10 Pm (f) attention was drawn to the activation of microglial cells and the accumulation of phagosomes in their cytoplasm (Fig. 4). In the cerebral cortex of OXYS rats treated with IQ-1S signs of microglial activation were much less common.

IQ-1S improved the rheological properties of blood.
In OXYS rats, the blood viscosity exceeded the values of this indicator in Wistar rats in the range of medium (45-90 s -1 ) and high (150-450 s -1 ) shear rates by 8-12% (Fig. 5). Factors that determine blood viscosity Table 1. IQ-1S suppresses destructive changes in neurons and glia in the sensorimotor cortex of OXYS rats Data are presented as M ± SEM (n = 10). The differences are significant: *, compared with Wistar rats (p < 0.05); +, compared with control OXYS rats (p < 0.05). include the hematocrit and plasma viscosity (macrorheological parameters), as well as erythrocyte aggregation and their deformability (microrheological parameters) [24]. The plasma viscosity and hematocrit in Wistar rats and control OXYS rats did not differ, but the erythrocyte deformability index in OXYS rats in the shear stress range of 7-20 Pa was significantly lower by 8-11% than in Wistar rats ( Table 3). The observed changes in hemorheological parameters generally coincide with the previously obtained data [16] and indicate the development of the high blood viscosity syndrome in OXYS rats, which leads to a decrease in the efficiency of oxygen transport by the blood. IQ-1S in OXYS rats did not affect the hematocrit, but at the same time reduced the content of fibrinogen in the blood plasma of OXYS rats by 22%, which was reflected in a decrease in plasma viscosity by 5% (Table 3). IQ-1S caused an increase in the index of erythrocyte deformability relative to the control by 17-20% (Table 3), reduced blood viscosity by 11-15% in the entire measured range of shear rates, and increased the index of oxygen delivery to tissues by 12-17% (Fig. 5).

DISCUSSION
The main goal of this study was to evaluate the preventive potential of IQ-1S, a new JNK inhibitor with an increased affinity for JNK3, and its ability to suppress neurodegenerative processes in OXYS rats at an early stage of development of AD signs. As early as at the age of 3-4 months, OXYS rats show signs of neurodegenerative changes: neuronal death, synaptic dysfunction, tau protein hyperphosphorylation, and mitochondrial dysfunction, which together lead to behavioral changes and memory impairment [14,25]. At the same time, the accumulation of amyloid beta occurs later than these manifestations of accelerated brain aging in OXYS rats; its pronounced increase is observed in the cerebral cortex and hippocampus of animals at the age of about 12 months [13]. Thus, at the beginning of the experiment, the corresponding pathomorphological signs of the disease were already 1 Pm (f) Fig. 3. The effect of IQ1-1S on the cerebral vessels of OXYS rats. Representative photographs of the vessels of Wistar rats (a), OXYS rats (b) and OXYS rats treated with IQ-1S (c). Capillaries in Wistar rats of a normal structure and filled with blood (black arrows), thrombosis of the capillary with destruction of endotheliocytes, edema of the perivascular space in OXYS rats (dashed arrow). Administration of IQ-1S reduces the degree of microcirculatory disorders in OXYS rats. Cresyl violet staining according to Nissl. d, Specific area of cerebral vessels. Data are presented as M ± SD (n = 10). The differences are significant: *, compared with Wistar rats (p < 0.05); +, compared with control OXYS rats (p < 0.05). present in OXYS rats, and the age from 4.5 to 6 months, during which OXYS rats received the JNK3 inhibitor IQ-1S, can be conditionally defined as the prodromal period of development of AD signs [26]. The results of this study are consistent with previously obtained data.
In the sensorimotor cortex of the brain of 6-monthold OXYS rats, we revealed pronounced neurodegenerative changes: increased neuronal death and signs of glia activation against the background of cerebrovascular disorders; disruptions of microvascularization and microcirculation (a decrease in the density of blood vessels and the appearance of a significant number of microvessels with signs of partial occlusion). Disturbances in the rheological properties of blood contribute to microcirculation disorders: a decrease in the deformability of erythrocytes and an increase in plasma viscosity, which ultimately manifests itself as an increase in the viscosity of whole blood and a decrease in oxygen delivery to tissues. The observed disturbances in the rheological properties of blood, microcirculation, and microvascularization in the brain tissue of OXYS rats can lead to a decrease in blood flow, to a discrepancy between the brain's need for oxygen and metabolic substrates and their supply, and, as a consequence, to neuronal dysfunction [27].
Our studies have shown that the course of administration of IQ-1S for a month and a half limited the development of neurodegenerative processes in the cerebral cortex of OXYS rats: it increased the proportion of unchanged neurons and reduced the proportion of neurons with signs of destruction and irreversible damage. At the same time, the specific number of neurons in the cortex of Wistar and OXYS rats did not differ. The method we used does not allow us to strictly determine the mechanisms of neuron death. At the same time, a significant decrease in the proportion of irreversibly damaged neurons (hyperchromic neurons with shrinking and neurons with signs of total chromatolysis) indicates that IQ-1S suppressed neuronal death in the sensorimotor cortex of OXYS rats [28]. Previously [29], in the prefrontal cortex of OXYS rats at the age of 20 days (at the presymptomatic stage), activation of apoptosis was detected, which the authors associated with a delay in brain maturation in OXYS rats. They also showed that the progression of AD-like pathology in OXYS rats is accompanied by  Oxygen delivery index, Ht%/mPa s Table 3. The influence of IQ-1S on plasma viscosity (PV, mPa s), hematocrit (Ht, %), plasma fibrinogen concentration (FG, g/L), and erythrocyte deformability index (EDI, rel. units at shear stress 7, 10 and 20 Pa) in OXYS rats Data are presented as M ± SEM (n = 5). The differences are significant: *, compared to Wistar rats (p < 0.05); + , compared to control OXYS rats (p < 0.05). Mitochondrial dysfunction is considered the most likely cause of premature aging in OXYS rats. Structural and functional changes in mitochondria in the brain of OXYS rats precede and accompany the development of AD signs, and actions aimed at restoring mitochondrial functions suppress and/or delay their development [30,31]. In the present study, we revealed significant disturbances in the ultrastructure of mitochondria and a significant decrease in their number in neurons of the sensorimotor cortex of the brain of OXYS rats compared with that of Wistar rats. IQ-1S significantly improved the ultrastructure of mitochondria but did not significantly affect their number. It also largely prevented the destruction of the granular ER and the activation of the lysosomal apparatus.
In recent years, there have been a growing number of arguments supporting the idea that glial changes that increase with age play a significant role in the pathogenesis of the sporadic form of AD [32]. Activation of glia can prevent the progression of AD by providing clearance of amyloid beta, while excessive activation of glia enhances its formation and the expression of pro-inflammatory cytokines in the brain [33]. Previously, it was shown that AD signs develop in OXYS rats under conditions of a decrease in the intensity of neurogenesis in the neurogenic niche of the hippocampus against the background of a reduced density of astrocytes, with insufficient glial support of neurons, while the progression of the disease takes place against the background of reactive astrogliosis and microglia activation in the hippocampus [34]. In the present study, we did not reveal an increase in the density of gliocytes in the sensorimotor cortex of the brain of 6-month-old OXYS rats, but the ratio of glial cells and neurons (glioneural index) was increased compared with Wistar rats, in all the studied cortical layers, which indicates the activation of glia. At the same time, at the electron microscopy level we observed phagocytosis of neurons by oligodendrocytes and the appearance of a large number of activated microgliocytes with numerous vacuoles and phagosomes in the cytoplasm. As is known, microglial activation is a common pathophysiological mechanism for the development of neurodegenerative diseases and often occurs in parallel with or precedes active neuronal death [35]. On the background of IQ-1S administration, in two of the three studied layers of the sensorimotor cortex of OXYS rats, the glioneural index returned to normal; microglia became less active. Previously, a decrease in the density of blood vessels and their ultrastructural anomalies were found in the hippocampus of 5-month-old OXYS rats during the period of active manifestation of AD signs, and significant cerebrovascular disorders occurred during their progression [15]. The results of our study con-firmed that cerebral blood flow disturbances make a significant contribution to the development of neurodegenerative processes in OXYS rats. We also showed that the neuroprotective effect of IQ-1S is largely due to a significant improvement in microcirculation in the cerebral cortex of animals, as evidenced by a doubling of the number of open functioning vessels. Obviously, the supply of oxygen to brain cells in rats treated with IQ-1S was also positively affected by the weakening of the hyperviscosity syndrome due to improved erythrocyte deformability, a decrease in fibrinogen content, and a decrease in plasma viscosity.
Thus, IQ-1S showed the ability to improve individual macro-and microrheological parameters and reduce the severity of the hyperviscosity syndrome in OXYS rats. We have previously demonstrated similar effects of IQ-1S in models of arterial hypertension and total transient cerebral ischemia [36,37]. It can be assumed that improvement in the rheological properties of blood can contribute to the neuroprotective effect of IQ-1S in OXYS rats. At the same time, it is clear that the effects of this JNK inhibitor were systemic.
JNK3, the key isoform of c-Jun N-terminal kinase in the CNS, is involved in brain development, neuronal functions, and responses to stress, and is a regulator of apoptosis signals [3]. As noted above, excessive activation of JNK3 is associated with neuronal death in AD; it also affects the accumulation of beta amyloid and tau hyperphosphorylation [4][5][6]. At the same time, there are no data on changes in the level and activity of JNK3 in the brain with age. One limitation of our study was the lack of assessment of both the level of JNK3 itself and any of its targets, the activity of the JNK signaling pathway in the cerebral cortex of animals, and the effect of IQ-1S on them. Nevertheless, the results we obtained indicate that an increase in the activity of the JNK signaling pathway contributes to the development of AD, including at the early stages of its development. We believe that the use of the JNK3 inhibitor IQ-1S may be a promising strategy for the prevention of early neurodegenerative disorders and, possibly, the treatment of AD. However, this will require detailed study of the mechanisms of action of IQ-1S. NEUROCHEMICAL

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