A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species.

Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIß subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIß-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIß is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIß-L50R mouse model. We define RIß-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIß dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIß-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIß-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

Maternal quercetin supplementation improved lipopolysaccharide-induced cognitive deficits and inflammatory response in a rat model of maternal immune activation.

BACKGROUND: There is strong evidence that prenatal infection during a specific period of brain development increases the risk of neurodevelopmental disorders, partly through immune-inflammatory pathways. This suggests that anti-inflammatory agents could prevent these disorders by targeting the maternal inflammatory response. In the present study, we used a rat model of maternal immune activation (MIA) to examine whether maternal quercetin (QE) supplementation can alleviate behavioral deficits and inflammatory mediators in the prefrontal cortex (PFC) and hippocampus of adult male offspring. METHODS: Pregnant rats were supplemented with QE (50 mg/kg) or vehicle throughout pregnancy and injected with either lipopolysaccharide (0.5 mg/kg) or saline on gestational days 15/16. At postnatal day 60, we evaluated the offspring's behavior, hippocampal and prefrontal cortex glial density, pro-inflammatory gene expression, and neuronal survival. RESULTS: Our data showed that maternal QE supplementation can prevent working and recognition memory impairments in adult MIA offspring. This behavioral improvement correlates with the decrease in MIA-induced expression of pro-inflammatory genes, microglia, and astrocyte densities, without affecting neuronal survival, in both PFC and CA1 hippocampus areas. CONCLUSION: Therefore, our study supports the potential preventive effect of QE on MIA-induced behavioral dysfunctions, at least in part, by suppressing the glial-mediated inflammatory response.

Amyloid-ß mediates intestinal dysfunction and enteric neurons loss in Alzheimer's disease transgenic mouse.

Alzheimer's disease (AD) is traditionally considered as a brain disorder featured by amyloid-ß (Aß) deposition. The current study on whether pathological changes of AD extend to the enteric nervous system (ENS) is still in its infancy. In this study, we found enteric Aß deposition, intestinal dysfunction, and colonic inflammation in the young APP/PS1 mice. Moreover, these mice exhibited cholinergic and nitrergic signaling pathways damages and enteric neuronal loss. Our data show that Aß42 treatment remarkably affected the gene expression of cultured myenteric neurons and the spontaneous contraction of intestinal smooth muscles. The intra-colon administration of Aß42 induced ENS dysfunction, brain gliosis, and ß-amyloidosis-like changes in the wild-type mice. Our results suggest that ENS mirrors the neuropathology observed in AD brains, and intestinal pathological changes may represent the prodromal events, which contribute to brain pathology in AD. In summary, our findings provide new opportunities for AD early diagnosis and prevention.

Retinal clues for selective neuronal loss in multiple sclerosis.

OBJECTIVE: The relationship between the cell body layer and the dendritic network layer of the retina and cognitive performance (CP) in MS patients has not been examined separately. The objective of this study is to predict cognitive impairment (CI) in RRMS patients and to examine the relationship between CP and ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL divided by IPL (GCL/IPL). METHODS: Ophthalmological evaluation, retinal segmentation, and Symbol Digit Modalities Test (SDMT) were performed on 102 RRMS patients and 54 healthy subjects. The relationships of GCL, IPL, and GCL/IPL with CP in eyes without a history of optic neuritis were investigated using Spearman's correlation. Models were created by accepting 1 standard deviation less of the SDMT mean of the control group as the limit for CI. The cutoff value of the GCL/IPL variable that could predict CI was calculated by ROC analysis, and the ability to accurately predict CI was tested with binary logistic regression. RESULTS: No correlation was found between OCT parameters and CP in healthy subjects. Correlation was found between GCL thickness and GCL/IPL variable and CP in RRMS patients (r=0.235, r=0.667 respectively). A GCL/IPL value of 1.255 was able to identify CI with 81.8% sensitivity and 75.9% specificity (AUC=0.844, LR=3.38) and predicted CI with 74.5% accuracy (Nagelkerke R2=0.439). CONCLUSION: In RRMS patients, the IPL thickness is unrelated to CP. Therewithal, the GCL/IPL-CP relationship is stronger than the GCL-CP relationship and GCL/IPL can predict CI.

scL-2PAM: A Novel Countermeasure That Ameliorates Neuroinflammation and Neuronal Losses in Mice Exposed to an Anticholinesterase Organophosphate.

Due to their inhibition of acetylcholinesterase, organophosphates are among the most toxic of chemicals. Pralidoxime (a.k.a 2-PAM) is the only acetylcholinesterase reactivator approved in the U.S., but 2-PAM only poorly traverses the blood-brain barrier. Previously, we have demonstrated that scL-2PAM, a nanoformulation designed to enter the brain via receptor-mediated transcytosis, is superior to unencapsulated 2-PAM for reactivating brain acetylcholinesterase, ameliorating cholinergic crisis, and improving survival rates for paraoxon-exposed mice. Here, we employ histology and transcriptome analyses to assess the ability of scL-2PAM to prevent neurological sequelae including microglial activation, expression of inflammatory cytokines, and ultimately loss of neurons in mice surviving paraoxon exposures. Levels of the mRNA encoding chemokine ligand 2 (CCL2) were significantly upregulated after paraoxon exposures, with CCL2 mRNA levels in the brain correlating well with the intensity and duration of cholinergic symptoms. Our nanoformulation of 2-PAM was found to be superior to unencapsulated 2-PAM in reducing the levels of the CCL2 transcript. Moreover, brain histology revealed that scL-2PAM was more effective than unencapsulated 2-PAM in preventing microglial activation and the subsequent loss of neurons. Thus, scL-2PAM appears to be a new and improved countermeasure for reducing neuroinflammation and mitigating brain damage in survivors of organophosphate exposures.

Neuronal loss and inflammation preceding fibrillary tau pathology in a rat model with early human-like tauopathy.

In tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), the microtubule associated protein tau undergoes conformational and posttranslational modifications in a gradual, staged pathological process. While brain atrophy and cognitive decline are well-established in the advanced stages of tauopathy, it is unclear how the early pathological processes manifest prior to extensive neurodegeneration. For these studies we have applied a transgenic rat model of human-like tauopathy in its heterozygous form, named McGill-R955-hTau. The goal of the present study was to investigate whether lifelong accumulation of mutated human tau could reveal the earliest tau pathological processes in a context of advanced aging, and, at stages before the overt aggregated or fibrillary tau deposition. We characterized the phenotype of heterozygous R955-hTau rats at three endpoints, 10, 18 and 24-26 months of age, focusing on markers of cognitive capabilities, progressive tau pathology, neuronal health, neuroinflammation and brain ultrastructural integrity, using immunohistochemistry and electron microscopy. Heterozygous R955-hTau transgenic rats feature a modest, life-long accumulation of mutated human tau that led to tau hyperphosphorylation and produced deficits in learning and memory tasks after 24 months of age. Such impairments coincided with more extensive tau hyperphosphorylation in the brain at residues pThr231 and with evidence of oligomerization. Importantly, aged R955-hTau rats presented evidence of neuroinflammation, detriments to myelin morphology and detectable hippocampal neuronal loss in the absence of overt neurofibrillary lesions and brain atrophy. The slow-progressing tauopathy of R955-hTau rats should allow to better delineate the temporal progression of tau pathological events and therefore to distinguish early indicators of tauopathy as having the capability to induce degenerative events in the aged CNS.

Neuroimmune Connections in Aging and Neurodegenerative Diseases.

In recent years, the inter-relationship between the innate immune system and the central nervous system (CNS) has moved to the forefront of biomedical research, with the discovery that these two physiological systems modulate each other by a steady mutual interaction. During normal brain aging, but also under certain pathological conditions, this crosstalk can go beyond physiological control, resulting in an unresolved inflammatory response of the CNS-resident immune cells that might initiate and propagate the progression of severe tissue damage and neurodegeneration. In this review, we focus on the impact of CNS-resident cells of the innate immune system for the development of neurodegenerative diseases, review immune pathway genes that have been identified, and discuss the vicious cycle between inflammation and neurodegeneration.

Patients who died with steatohepatitis or liver cirrhosis show neuroinflammation and neuronal loss in hippocampus.

BACKGROUND: Neuroinflammation in the cerebral cortex of patients who died with liver cirrhosis and neuroinflammation, and neuronal death in the cerebellum of patients who died with steatohepatitis or cirrhosis, were reported. Hippocampal neuroinflammation could contribute to cognitive decline in patients with liver disease, but this has yet to be studied. The study aims were to assess if hippocampus from patients who died with steatohepatitis or cirrhosis showed: (i) glial activation, (ii) altered cytokine content, (iii) immune cell infiltration, (iv) neuronal apoptosis and (v) neuronal loss. METHODS: Post-mortem hippocampus was obtained from 6 controls, 19 patients with steatohepatitis (SH) and 4 patients with liver cirrhosis. SH patients were divided into SH1 (n = 9), SH2 (n = 6) and SH3 (n = 4) groups depending on disease severity. Glial activation, IL-1ß and TNFα content, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss were analyzed by immunohistochemistry. RESULTS: Patients who died in SH1 showed astrocyte activation, whereas those who died in SH2 also showed microglial activation, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss. These changes remained in patients in SH3, who also showed increased IL-1ß and TNFα. Patients who died of liver cirrhosis did not show CD4 lymphocyte infiltration, neuronal apoptosis or increase in TNFα, but still showed glial activation, increased IL-1ß and neuronal loss. CONCLUSIONS: Patients with steatohepatitis showed glial activation, immune cell infiltration, apoptosis and neuronal loss. Glial activation and neuronal loss remained in cirrhotic patients. This may explain the irreversibility of some cognitive alterations in hepatic encephalopathy. Cognitive reserve may contribute to different grades of cognitive impairment despite similar neuronal loss.

Recent advances to Neuroprotection: repurposing drugs against neuroinflammatory disorders.

Cell death is a natural mechanism for biological clearance for the maintenance of homeostasis in a dynamic microenvironment of the central nervous system. Stress and various factors can lead to imbalance between cellular genesis and cell death leading to dysfunctionality and a number of neuropathological disorders. Drug repurposing can help bypass development time and cost. A complete understanding of drug actions and neuroinflammatory pathways can lead to effective control of neurodegenerative disorders. This review covers recent advances in various neuroinflammatory pathways understanding, biomarkers, and drug repurposing for neuroprotection.

NLRP3 deficiency protects against hypobaric hypoxia induced neuroinflammation and cognitive dysfunction.

As increasing number of people migrated to high altitude, highland encephalopathy and hypoxia-induced cognitive impairment arouse public attention. Yet, its underlying mechanisms remain unclear. Emerging evidence has implied neuroinflammation and neuronal loss may be involved. In the present study, we investigated the neuroinflammation and neuronal loss in mice after hypoxic insult. Our reports showed hypobaric hypoxia exposure for 3 weeks led to impaired spatial exploration and short-term memory in mice, concomitant with neuron loss. In addition, hypoxia induced neuroinflammation and NLRP3 inflammasome activation. Besides, to explore the role of the inflammasome in hypoxia-induced cognitive dysfunction, NLRP3 knockout mice were applied and the results showed that NLRP3 could negatively regulate GPX4 to modify antioxidant capacity. In summary, our work demonstrated that hypoxia exposure led to neuroinflammation and neuronal-deletion, which may be the key events in the process of hypoxia induced cognitive impairment. NLRP3 inflammasome promoted antioxidant deficiency by negatively regulating GPX4.

Antiepileptogenic Effects of Anakinra, Lamotrigine and Their Combination in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Beneficial Effects of Probiotic Bifidobacterium longum in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats.

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, a probiotic, on inflammation, neuronal degeneration, and behavior are evaluated in a lithium-pilocarpine model of temporal lobe epilepsy (TLE) induced in young adult rats. B. longum was administered orally at a dose of 109 CFU/rat for 30 days after pilocarpine injection. The results show that B. longum treatment has beneficial effects on the TLE-induced changes in anxiety levels, neuronal death in the amygdala, and body weight recovery. In addition, B. longum increased the expression of anti-inflammatory and neuroprotective genes, such as Il1rn and Pparg. However, the probiotic had little effect on TLE-induced astrogliosis and microgliosis and did not reduce neuronal death in the hippocampus and temporal cortex. The study suggests that B. longum may have a beneficial effect on TLE and may provide valuable insights into the role of gut bacteria in epileptogenesis. In addition, the results show that B. longum may be a promising drug for the comprehensive treatment of epilepsy.

Nicotinamide reverses deficits in puberty-born neurons and cognitive function after maternal separation.

BACKGROUND: Early life stress (ELS) is associated with the development of schizophrenia later in life. The hippocampus develops significantly during childhood and is extremely reactive to stress. In rodent models, ELS can induce neuroinflammation, hippocampal neuronal loss, and schizophrenia-like behavior. While nicotinamide (NAM) can inhibit microglial inflammation, it is unknown whether NAM treatment during adolescence reduces hippocampal neuronal loss and abnormal behaviors induced by ELS. METHODS: Twenty-four hours of maternal separation (MS) of Wistar rat pups on post-natal day (PND)9 was used as an ELS. On PND35, animals received a single intraperitoneal injection of BrdU to label dividing neurons and were given NAM from PND35 to PND65. Behavioral testing was performed. Western blotting and immunofluorescence staining were used to detect nicotinamide adenine dinucleotide (NAD+)/Sirtuin3 (Sirt3)/superoxide dismutase 2 (SOD2) pathway-related proteins. RESULTS: Compared with controls, only MS animals in the adult stage (PND56-65) but not the adolescent stage (PND31-40) exhibited pre-pulse inhibition deficits and cognitive impairments mimicking schizophrenia symptoms. MS decreased the survival and activity of puberty-born neurons and hippocampal NAD+ and Sirt3 expression in adulthood. These observations were related to an increase in acetylated SOD2, microglial activation, and significant increases in pro-inflammatory IL-1ß, TNF-α, and IL-6 expression. All the effects of MS at PND9 were reversed by administering NAM in adolescence (PND35-65). CONCLUSIONS: MS may lead to schizophrenia-like phenotypes and persistent hippocampal abnormalities. NAM may be a safe and effective treatment in adolescence to restore normal hippocampal function and prevent or ameliorate schizophrenia-like behavior.

Multimodal magnetic resonance imaging quantification of gray matter alterations in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder.

Herein, we combined neurite orientation dispersion and density imaging (NODDI) and synthetic magnetic resonance imaging (SyMRI) to evaluate the spatial distribution and extent of gray matter (GM) microstructural alterations in patients with relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica spectrum disorder (NMOSD). The NODDI (neurite density index [NDI], orientation dispersion index [ODI], and isotropic volume fraction [ISOVF]) and SyMRI (myelin volume fraction [MVF]) measures were compared between age- and sex-matched groups of 30 patients with RRMS (6 males and 24 females; mean age, 51.43 ± 8.02 years), 18 patients with anti-aquaporin-4 antibody-positive NMOSD (2 males and 16 females; mean age, 52.67 ± 16.07 years), and 19 healthy controls (6 males and 13 females; mean age, 51.47 ± 9.25 years) using GM-based spatial statistical analysis. Patients with RRMS showed reduced NDI and MVF and increased ODI and ISOVF, predominantly in the limbic and paralimbic regions, when compared with healthy controls, while only increases in ODI and ISOVF were observed when compared with NMOSD. Compared to NDI and MVF, the changes in ODI and ISOVF were observed more widely, including in the cerebellar cortex. These abnormalities were associated with disease progression and disability. In contrast, patients with NMOSD only showed reduced NDI mainly in the cerebellar, limbic, and paralimbic cortices when compared with healthy controls and patients with RRMS. Taken together, our study supports the notion that GM pathologies in RRMS are distinct from those of NMOSD. However, owing to the limitations of the study, the results should be cautiously interpreted.

The anticonvulsant effect of chronic treatment with topiramate after pilocarpine-induced status epilepticus is accompanied by a suppression of comorbid behavioral impairments and robust neuroprotection in limbic regions in rats.

Epilepsy is a widespread neurological disorder frequently associated with a lot of comorbidities. The present study aimed to evaluate the effects of the antiseizure medication topiramate (TPM) on spontaneous motor seizures, the pathogenesis of comorbid mood and cognitive impairments, hippocampal neuronal loss, and oxidative stress and inflammation in a rat model of temporal lobe epilepsy (TLE). Vehicle/TPM treatment (80 mg/kg, p.o.) was administered 3 h after the pilocarpine (pilo)-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. The chronic TPM treatment caused side effects in naïve rats, including memory disturbance, anxiety, and depressive-like responses. However, the anticonvulsant effect of this drug, administered during epileptogenesis, was accompanied by beneficial activity against comorbid behavioral impairments. The drug treatment suppressed the SE-induced neuronal damage in limbic structures, including the dorsal (CA1 and CA2 subfield), the ventral (CA1, CA2 and CA3) hippocampus, the basolateral amygdala, and the piriform cortex, while was ineffective against the surge in the oxidative stress and inflammation. Our results suggest that neuroprotection is an essential mechanism of TPM against spontaneous generalized seizures and concomitant emotional and cognitive impairments.

High fructose diet-induced obesity worsens post-ischemic brain injury in the hippocampus of female rats.

Objectives: Cerebral ischemia is caused by a reduction of the blood flow in a specific area in the brain, triggering cellular cascades in the tissue that result in neuronal death. This phenomenon leads to neurological decline in patients with stroke. The extent of the injury after stroke could be related to the condition of obesity. Thus, we aim to analyze the effect of obesity induced by a high fructose diet (HFD) on the brain after cerebral ischemia in rats.Methods: We induced the obesity model in female Wistar rats with 20% fructose in water for 11 weeks. We then performed cerebral ischemia surgery (2-vessel occlusion), carried out the neurological test 6, 24 and 48 h post-ischemia and analyzed the histological markers.Results: The HFD induced an obese phenotype without insulin resistance. The obese rats exhibited worse neurological performance at 6 h post-ischemia and showed neuronal loss and astroglial and microglial immunoreactivity changes in the caudate putamen, motor cortex, amygdala and hippocampus at 48 h post-ischemia. However, the most commonly affected area was the hippocampus, where we found an increase in interleukin 1ß in the blood vessels of the dentate gyrus, a remarkable disruption of MAP-2+ dendrites, a loss of brain-derived neurotrophic factor and the presence of PHF-tau. In conclusion, a HFD induces an obese phenotype and worsens the neuronal loss, inflammation and plasticity impairment in the hippocampus after cerebral ischemia.

Asiatic acid attenuates aluminium chloride-induced behavioral changes, neuronal loss and astrocyte activation in rats.

Aluminium (Al) is a potent neurotoxic metal known to cause neurodegeneration. Al exposure causes oxidative stress by accumulation of reactive oxygen species, followed by the activation of neuronal cell death in the brain. Asiatic acid (AA), the major bioactive compound of Centella asiatica (a medicinal plant), act as multifunctional drug as well as an antioxidant. Thus, the present study aimed to investigate the potential neuroprotective effect of AA against Al neurotoxicity. Rats were orally administered aluminium chloride (AlCl3; 100 mg/kg b. wt.) dissolved in distilled water for 8 weeks or AA (75 mg/kg b. wt.) in combination with AlCl3. The results showed that AlCl3-intoxication causes significant impairment of memory, enhances anxiety-like behavior, acetyl cholinesterase (AChE) activity, malondialdehydes (MDA) level, and concomitant decrease in the activities of superoxide dismutase (SOD) and catalase (CAT) in the cortex and hippocampus regions of rat brain. In addition, AlCl3-intoxication enhanced neuronal loss and reactive astrogliosis in both regions. However, co-administration of AA with AlCl3 significantly attenuated the behavioral alterations, restored SOD and CAT activities, while reduced AChE activity and MDA content. Further, the study demonstrated that AA attenuates neuronal loss and reactive astrogliosis in rat brain. In conclusion, the study suggests that AA protects rat brain from Al neurotoxicity by inhibiting oxidative stress, neuronal loss and reactive astrogliosis.

Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain.

After stroke, there is a delayed neuronal loss in brain areas surrounding the infarct, which may in part be mediated by microglial phagocytosis of stressed neurons. Microglial phagocytosis of stressed or damaged neurons can be mediated by UDP released from stressed neurons activating the P2Y6 receptor on microglia, inducing microglial phagocytosis of such neurons. We show evidence here from a small trial that the knockout of the P2Y6 receptor, required for microglial phagocytosis of neurons, prevents the delayed neuronal loss after transient, focal brain ischemia induced by endothelin-1 injection in mice. Wild-type mice had neuronal loss and neuronal nuclear material within microglia in peri-infarct areas. P2Y6 receptor knockout mice had no significant neuronal loss in peri-infarct brain areas seven days after brain ischemia. Thus, delayed neuronal loss after stroke may in part be mediated by microglial phagocytosis of stressed neurons, and the P2Y6 receptor is a potential treatment target to prevent peri-infarct neuronal loss.

MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium-Pilocarpine Model of Epilepsy.

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium-pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium-pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.

Neurodegenerative disorders: Are we wrong?

It is not obvious how to define a neurodegenerative disorder. There are several challenging questions: How should the diagnosis be made? How can we be sure that symptoms do not simply reflect normal aging of the nervous system? What are the mechanisms and what are the causes? What are the perspectives of treatment for the patients? Today, given the repetitive failures of curative and preventive treatments, the purpose of the following remarks is not to provide an additional lesson on "how to find a new treatment". Instead, the aim is to ask the difficult questions that might lead to envisaging research from another angle.