Synthesis of novel silica encapsulated spiropyran-based thermochromic materials.

A series of novel spiropyrans were synthesized through the condensation of substituted 3,3-dimethyl-2-methyleneindoline with different nitro-substituted o-hydroxy aromatic aldehydes. Indoles were initially substituted with a variety of alkanes and esters moieties. The substituted 3,3-dimethyl-2-methyleneindoline was then reacted with nitro-substituted o-hydroxy aromatic aldehydes to yield the respective spiropyrans. The synthesized novel spiropyrans were encapsulated in silica nano-shells to protect them from the effect of moisture and pH. The thermochromic behaviour of novel spiropyrans was studied by UV-visible spectroscopy. The thermally induced isomerization of spiropyran derivatives was carried out in a water/ethanol mixture. The thermal isomerization of spiro-heterocyclic (colourless form) to merocyanine (MC) (coloured form) was a discontinuous process and was observed in a temperature range of 5-60°C via UV-visible spectrometer. The absorption process occurs reversibly regardless of the heating/cooling sequence. The spiropyran derivatives, therefore, have a potential application for colorimetric temperature indication.

Blood-Based Biomarkers for Predictive Diagnosis of Cognitive Impairment in a Pakistani Population.

Numerous studies have identified an association between age-related cognitive impairment (CI) and oxidative damage, accumulation of metals, amyloid levels, tau, and deranged lipid profile. There is a concerted effort to establish the reliability of these blood-based biomarkers for predictive diagnosis of CI and its progression. We assessed the serum levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, total cholesterol, selected metals (Cu, Al, Zn, Pb, Mn, Cad), and total-tau and amyloid beta-42 protein in mild (n = 71), moderate (n = 86) and severe (n = 25) cognitively impaired patients and compared them with age-matched healthy controls (n = 90) from Pakistan. We found that a decrease in HDL cholesterol (correlation coefficient r = 0.467) and amyloid beta-42 (r = 0.451) were associated with increased severity of CI. On the other hand, an increase in cholesterol ratio (r = -0.562), LDL cholesterol (r = -0.428), triglycerides, and total-tau (r = -0.443) were associated with increased severity of CI. Increases in cholesterol ratio showed the strongest association and correlated with increases in tau concentration (r = 0.368), and increased triglycerides were associated with decreased amyloid beta-42 (r = -0.345). Increased Cu levels showed the strongest association with tau increase and increased Zn and Pb levels showed the strongest association with reduced amyloid beta-42 levels. Receiver Operating Characteristic (ROC) showed the cutoff values of blood metals (Al, Pb, Cu, Cad, Zn, and Mn), total-tau, and amyloid beta-42 with sensitivity and specificity. Our data show for the first time that blood lipids, metals (particularly Cu, Zn, Pb, and Al), serum amyloid-beta-42/tau proteins modulate each other's levels and can be collectively used as a predictive marker for CI.

Co-exposure of metals and high fat diet causes aging like neuropathological changes in non-aged mice brain.

In recent decades, humans' exposure to metals have increased due to industrialization and socioeconomic trends have caused increased high fat diet (HFD) consumption. Concurrently, metals and HFD are risk factors for health, and in particular, the cognitive impairment. The aim of this study was to evaluate the effect of metals and HFD treatment on neuropathological changes in young mice brain, and compare with untreated young mice (8-11 weeks = 2-3 months) and aged mice (12 months). Mice were given 300 ppm of Aluminum (Al), Copper (Cu), Lead (Pb) and Cadmium (Cd) in drinking water and HFD feed (40% of the feed weight was animal fat) for 42 days. Metals+HFD treated mice were subjected to behavior tests, such as, Morris water maze, elevated plus maze, fear condition and contextual memory to evaluate memory levels. Spatial memory (p < 0.01), contextual memory (p < 0.01) and fear memory (p < 0.05) were significantly impaired in metals+HFD group compared to young mice. The extent of neurodegeneration with metals+HFD co-exposure was considerably high in hippocampus (p < 0.01) and cortex (p < 0.01), compared to aged mice brain and untreated young mice. Increased oxidative stress was recorded in the cortex, hippocampus and amygdala of metals+HFD group compared to the young (p < 0.001) and aged group (p < 0.05). The acetylcholine concentration decreased in cortex, hippocampus and amygdala of metals+HFD group, explaining the cholinergic deficits that caused cognitive impairment. Among the studied metals, Al was found to be highly accumulated in cortex (p < 0.01), hippocampus (p < 0.01) and amygdala (p < 0.01); followed by Pb, Cu and Cd. Hippocampus showed greater accumulation of metals than the cortex and amygdala. This data provided the novel evidences that combined administration of metals and HFD enhanced aging process, caused memory impairment, cholinergic hypofunction, elevated oxidative stress and neurodegeneration in young mice.

Elevated heavy metals levels in cognitively impaired patients from Pakistan.

The deficit in the visuospatial skills, thinking, learning and memory is termed as cognitive impairment. Human exposure to heavy metals is a potential risk factor for developing cognitive impairment. This study aimed to investigate the possible association between the concentration of heavy metals and the extent of cognitive impairment. Blood samples were subjected to microwave assisted acid digestion and evaluated for metals levels using atomic absorption spectrophotometry. We measured the levels of Cu, Pb, Al, Zn, Cd and Mn in 183 patients diagnosed with cognitive impairment; mild (n = 72), moderate (n = 86) and severe (n = 25) and compared them to age-matched healthy controls (n = 90). Results showed that all the aforementioned elements were significantly higher in cognitively impaired patients and increasing concentration was strongly correlated with increase in severity of the disease. The correlation study has shown that among the studied metals, Al and Cu are strongly associated with the cognitive impairment. This suggests the need for decrease in metal exposure to humans from environment, food and industries.

Pharmacological Effects of Turmeric on Learning, Memory and Expression of Muscarinic Receptor Genes (M1, M3 and M5) in Stress-induced Mouse Model.

BACKGROUND: Stress is involved in memory impairment through multiple mechanisms, including activation of hypothalamic-pituitary axis, which in turn activates release of corticosterone in blood. Cholinergic system blockade by the muscarinic antagonist, scopolamine, also impairs memory. OBJECTIVE: This study aimed to investigate the effect of turmeric (20mg/kg) on learning and memory and cholinergic system in a mouse model of stress along with cholinergic blockade. METHODS: Restrained stress was induced and cholinergic receptors were blocked using scopolamine in mice. Animals were treated with turmeric (turmeric rhizome powder which was also subjected to NMR analyses) and learning and social behavior was examined. Effect of turmeric on cholinergic muscarinic receptors (mAChR; M1, M3 and M5) gene expression was assessed by RT-PCR in both pre-frontal cortex and hippocampus. RESULTS: Ar-turmerone, curcuminoids and α-linolenic acid were the lead compounds present in turmeric extract. Increased serum corticosterone levels were observed in stressed mice when compared to the control group, while turmeric treatment significantly reduced serum corticosterone level. Turmeric treatment caused an improved learning and memory in Morris water maze test in stressed animals. Social novelty preference was also restored in turmeric treated animals. Following turmeric treatment, M5 expression was improved in the cortex and M3 expression was improved in the hippocampus of stress + scopolamine + turmeric treated group. CONCLUSIONS: These findings highlight the therapeutic role of turmeric by increasing the expression of M3, M5 and improving learning and memory. Turmeric can be an effective candidate for the treatment of amnesia caused by the stress.

Aluminum-Induced Cholinergic Deficits in Different Brain Parts and Its Implications on Sociability and Cognitive Functions in Mouse.

Aluminum is associated with etiology of many neurodegenerative diseases specially Alzheimer's disease. Chronic exposure to aluminum via drinking water results in aluminum deposition in the brain that leads to cognitive deficits. The study aimed to determine the effects of aluminum on cholinergic biomarkers, i.e., acetylcholine level, free choline level, and choline acetyltransferase gene expression, and how cholinergic deficit affects novel object recognition and sociability in mice. Mice were treated with AlCl3 (250 mg/kg). Acetylcholine level, free choline level, and choline acetyltransferase gene expression were determined in cortex, hippocampus, and amygdala. The mice were subjected to behavior tests (novel object recognition and social novelty preference) to assess memory deficits. The acetylcholine level in cortex and hippocampus was significantly reduced in aluminum-treated animals, as compared to cortex and hippocampus of control animals. Acetylcholine level in amygdala of aluminum-treated animals remained unchanged. Free choline level in all the three brain parts was found unaltered in aluminum-treated mice. The novel object recognition memory was severely impaired in aluminum-treated mice, as compared to the control group. Similarly, animals treated with aluminum showed reduced sociability compared to the control mice group. Our study demonstrates that aluminum exposure via drinking water causes reduced acetylcholine synthesis in spite of normal free choline availability. This deficit is caused by reduced recycling of acetylcholine due to lower choline acetyltransferase level. This cholinergic hypofunction leads to cognitive and memory deficits. Moreover, hippocampus is the most affected brain part after aluminum intoxication.

Memory Enhancing Effect of Black Pepper in the AlCl3 Induced Neurotoxicity Mouse Model is Mediated Through Its Active Component Chavicine.

UNLABELLED: Black pepper (Piper nigrum Linn.) has vital pharmacological properties with profound effects on central nervous system. Neurotoxic agents like Aluminum Chloride (AlCl3) cause the oxidative stress and result in improper processing of amyloid proteins leading to accumulation of amyloid ß plaques. AIM: The study aimed to explore the neuroprotective potential of black pepper (BP) extract (12.5mg/kg/day) on memory enhancement and its effect on expression of amyloid precursor protein (APP) isoforms (APP770 and APP695) in AlCl3 induced neurotoxicity (250mg/kg) mouse model. The study included the isolation and identification of pure compound from BP (chavicine) which was found pharmacologically active. METHODS: Morris water maze test, elevated plus maze, fear conditioning, context and cue dependent test and social preference tests were performed to investigate the learning and memory. Gene expression (APP isoforms) and in-vitro and ex-vivo DPPH free radical scavenging activity were performed to evaluate the role of BP. RESULTS: BP significantly improved memory in AlCl3 induced neurotoxicity mouse model along with effectively decreasing the expression of APP770 (amyloidogenic) isoform and improved level of APP695 (non-amyloidogenic) in hippocampus, amygdala and cortex. Fear extinction learning was considerably improved in BP treated group (7.83±2.03) than AlCl3 induced neurotoxicity group (39.75±4.25). In the hippocampus, BP significantly reduced the expression of APP770 (0.37±0.05) as compared to AlCl3 induced neurotoxicity group (0.72±0.06), and effectively increased (34.80±1.39) the percentage inhibition of DPPH free radicals as compared to AlCl3 induced neurotoxicity group (14±2.68). CONCLUSION: The study revealed that BP improves memory and chavicine is a lead compound producing pharmacological effects of BP.

Alpha-lipoic acid-mediated activation of muscarinic receptors improves hippocampus- and amygdala-dependent memory.

Aluminum (Al) is a neurotoxic agent which readily crosses the blood-brain-barrier (BBB) and accumulates in the brain leading to neurodegenerative disorders, characterised by cognitive impairment. Alpha-lipoic acid (ALA) is an antioxidant and has a potential to improve cognitive functions. This study aimed to evaluate the neuroprotective effect of ALA in AlCl3-induced neurotoxicity mouse model. Effect of ALA (25mg/kg/day) was evaluated in the AlCl3-induced neurotoxicity (AlCl3 150 mg/kg/day) mouse model on learning and memory using behaviour tests and on the expression of muscarinic receptor genes (using RT-PCR), in hippocampus and amygdala. Following ALA treatment, the expression of muscarinic receptor genes M1, M2 and choline acetyltransferase (ChaT) were significantly improved (p<0.05) relative to AlCl3-treated group. ALA enhanced fear memory (p<0.01) and social novelty preference (p<0.001) comparative to the AlCl3-treated group. Fear extinction memory was remarkably restored (p<0.001) in ALA-treated group demonstrated by reduced freezing response as compared to the AlCl3-treated group which showed higher freezing. In-silico analysis showed that racemic mixture of ALA has higher binding affinity for M1 and M2 compared to acetylcholine. These novel findings highlight the potential role of ALA in cognitive functions and cholinergic system enhancement thus presenting it an enviable therapeutic candidate for the treatment of neurodegenerative disorders.