Neuroprotective Effect of α-Mangostin in Ameliorating Propionic Acid-Induced Experimental Model of Autism in Wistar Rats

Several studies have documented the role of hyper-activation of extracellular signal-regulated kinases (ERK) in Autism pathogenesis. Alpha-mangostin (AMG) is a phytoconstituents with anti-oxidants, anti-inflammatory, and ERK inhibition properties in many diseases. Our research aims to investigate the neuroprotective effect of AMG in the rat model of intracerebroventricular-propionic acid (ICV-PPA) induced autism with a confirmation of its effect on the ERK signaling. Autism was induced in Wistar rats (total 36 rats; 18 male/18 female) by multiple doses of PPA through ICV injection for 11 days. Actophotometer and beam walking tasks were used to evaluate animals’ motor abilities, and the Morris water maze task was utilized to confirm the cognition and memory in animals. Long term administration of AMG100 mg/kg and AMG200 mg/kg continued from day 12 to day 44 of the experiment. Before that, animals were sacrificed, brains isolated, morphological, gross pathological studies were performed, and neurochemical analysis was performed in the brain homogenates. Cellular and molecular markers, including ERK, myelin basic protein, apoptotic markers including caspase-3, Bax, Bcl-2, neuroinflammatory markers, neurotransmitters, and oxidative stress markers, have been tested throughout the brain. Thus, AMG reduces the overactivation of the ERK signaling and also restored autism-like behavioral and neurochemical alterations.

D-galactose induced dysfunction in mice hippocampus and the possible antioxidant and neuro-modulatory effects of selenium

Aging is an ultimate reality that everyone has to face. D-galactose (D-gal) has been used extensively to develop aging model. Trace elements such as selenium (Sel) have been used as a potential antioxidant for neuro-protection. The present work aims to develop therapeutic agents such as Sel for the treatment of aging-induced neurological ailments such as anxiety, depression, and memory impairment. For this purpose, mice were treated with D-gal at a dose of 300 mg/ml/kg and various doses of Sel (0.175 and 0.35mg/ml/kg) for 28 days. Behavioural tests were monitored after treatment days. After the behavioural assessment mice were decapitated and their brains were collected. Hippocampi were removed from the brain for biochemical and neurochemical analysis. The present findings of behavioural analysis showed that D-gal induced anxiety and depression-like symptoms were inhibited by both doses of Sel. D-gal induced memory alteration was also prevented by repeated doses (0.175 and 0.35mg/ml/kg) of Sel. Biochemical analysis showed that D-gal induced increase of oxidative stress marker and decrease of antioxidant enzymes in the hippocampus was prevented by Sel administration. An increase in the activity of acetylcholinesterase was also diminished by Sel. The neurochemical assessment showed that D-gal induced increased serotonin metabolism and decreased acetylcholine levels in the hippocampus were restored by repeated treatment of Sel. It is concluded that D-gal induced dysfunction in mice hippocampus caused anxiety, depression, memory impairment, oxidative stress that were mitigated by Sel via its antioxidant potential and modulating capability of serotonergic and cholinergic functions.

Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage

HIV-1 infection affects approximately 37 million individuals and approximately 50% of seropositive individuals will develop symptoms of clinical depression and apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1 induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.

Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis

A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71–84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone—but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.

Evaluation of neuroprotective potential of methanolic extract of Hemidesmus indicus extract in Aβ (1-42) induced rats

Excessive cerebral deposition of amyloid-beta (Aβ) peptides with 40-42 amino acids are the major neuropathologic feature of Alzheimer's Disease (AD), accompanied by a progressive and functional decline in cognition. With the failing attempts in the development of new pharmacological intervention and due to suboptimal results from the existing therapies available for the treatment of AD, there is a constant hunt for a new therapeutic alternative to address this severe neurodegenerative disease. The present study aimed to investigate the neuroprotective effect of Hemidesmus indicus extract in Aβ (1-42) infused model of AD. Sporadic model of AD was achieved by intracerebroventricular (i.c.v) injection of Aβ (1-42) peptide in Wistar rats, followed by treatment with methanolic extract of H. indicus (MEHI) at 100 and 200 mg/kg for 28 days. Locomotor activity, Radial arm Maze task and Passive avoidance test were used for the assessment of neurobehavioral deficits. After completion of 28 days treatment protocol, animals were euthanized and brains were collected for neurochemical analysis. Reversal of cognitive impairment was observed by MEHI on Aβ (1-42) rats, as evidenced by improved spatial memory learning. Furthermore, MEHI attenuated Aβ (1-42) induced oxidative stress and inhibited acetylcholine esterase (AChE) activity. Collectively, these findings exhibited neuroprotective activity of MEHI by ameliorating Aβ (1-42) mediated neuronal damage, thereby can stand as a potential disease-modifying therapeutic for curbing AD pathology.

Hippocampal hub neurons maintain distinct connectivity throughout their lifetime

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as ‘hubs’ by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during locomotion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.

Hippocampal hub neurons maintain unique functional properties throughout their lifetime

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as ‘hubs’ by orchestrating neuronal dynamics. However, their fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs signal a variety of network states, including the activation of local CA1 assemblies. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.