Oxidative stress with a depletion of glutathione is a key factor in the initiation and progression of Alzheimer’s disease (AD). N-Acetylcysteine (NAC), a glutathione precursor, provides neuroprotective effects in AD animal models. Its amide form, N-Acetylcysteine amide (NACA), has an extended bioavailability compared to NAC. This study evaluates the neuroprotective effects of NACA against Aβ1-42 peptide-induced AD-like pathology in rats. Male Wistar rats (2.5 months old) were divided into five groups: Normal Control (NC), Sham (SH), Aβ, Aβ + NACA and NACA + Aβ + NACA (n = 8 in all groups). AD-like pathology was induced by the intracerebroventricular infusion of Aβ1-42 peptide into the lateral ventricle. NACA (75 mg/kg) was administered either as a restorative (i.e., injection of NACA for 7 consecutive days after inducing AD-like pathology (Aβ + N group)), or as prophylactic (for 7 days before and 7 days after inducing the pathology (N + Aβ + N group)). Learning and memory, neurogenesis, expression of AD pathology markers, antioxidant parameters, neuroprotection, astrogliosis and microgliosis were studied in the hippocampus and the prefrontal cortex. All data were analyzed with a one-way ANOVA test followed by Bonferroni’s multiple comparison test. NACA treatment reversed the cognitive deficits and reduced oxidative stress in the hippocampus and prefrontal cortex. Western blot analysis for Tau, Synaptophysin and Aβ, as well as a histopathological evaluation through immunostaining for neurogenesis, the expression of neurofibrillary tangles, β-amyloid peptide, synaptophysin, neuronal morphology and gliosis, showed a neuroprotective effect of NACA. In conclusion, this study demonstrates the neuroprotective effects of NACA against β-amyloid induced AD-like pathology.

Objectives Neuro-inflammation occurs as a sequence of brain injury and is associated with production of cytokines. Cytokines can modulate the function and survival of neurons, microglia and astrocytes. The objective of this study is to examine the effect of TNF on the neurons, microglia and astrocytes in normal brain and stab wound brain injury. Methods Normal BALB/c male mice (N) without any injury were subdivided into NA and NB groups. Another set mouse was subjected to stab wound brain injury (I) and were subdivided into IA and IB. NA and IA groups received intraperitoneal injections of TNF (1 µg/kg body weight/day) for nine days, whereas NB and IB groups received intraperitoneal injections of PBS. Animals were killed on 1^st, 2^nd, 3^rd, 7^th, and 9^th day. Frozen brain sections through the injury site in IA and IB or corresponding region in NA and NB groups were stained for neurodegeneration, immunostained for astrocytes, microglia and neurons. Western blotting for GFAP and ELISA for BDNF were done from the tissues collected from all groups. Results The number of degenerating neurons significantly decreased in TNF treated groups. There was a significant increase in the number of astrocytes and microglia in TNF treated groups compared to PBS treated groups. In addition, it was found that TNF stimulated the expression of GFAP and BDNF in NA and IA groups. Conclusions TNF induces astrogliosis and microgliosis in normal and injured brain and promotes the survival of cortical neurons in stab wound brain injury, may be by upregulating the BDNF level.

Neuro-inflammation is associated with the production of cytokines, which influence neuronal and glial functions. Although the proinflammatory cytokines interferon-γ (IFN-γ) and interleukin-1Beta (IL-1β) are thought to be the major mediators of neuro-inflammation, their role in brain injury remains ill-defined. The objective of this study was to examine the effect of IFN-γ and IL-1β on survival of cortical neurons in stab wound injury in mice. A stab wound injury was made in the cortex of male BALB/c mice. Injured mice (I) were divide into IFN-γ and IL-1β treatment experiments. Mice in I + IFN-γ group were treated with IFN-γ (ip, 10 µg/kg/day) for 1, 3 and 7 days and mice in I + IL-1β group were treated with 5 IP injection of IL-1β (0.5 µg /12 h). Appropriate control mice were maintained for comparison. Immunostaining of frozen brain sections for astrocytes (GFAP), microglia (Iba-1) and Fluoro-Jade B staining for degenerating neurons were used. Western blotting and ELISA for brain-derived neurotrophic factor (BDNF) were done on the tissues isolated from the injured sites. Results showed a significant increase in the number of both astrocytes and microglia in I + IFN-γ and I + IL-1β groups. There were no significant changes in the number of astrocytes or microglia in noninjury groups (NI) treated with IFN-γ or IL-1β. The number of degenerating neurons significantly decreased in I + IFN-γ and I + IL-1β groups. GFAP and BDNF levels were significantly increased in I + IFN-γ and I + IL-1β groups. Interferon-γ and IL-1β induce astrogliosis, microgliosis, enhance the secretion of BDNF, one of the many neurotrophic factors after brain injury, and promote the survival of cortical neurons in stab wound brain injury.

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain’s adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain.

Background: The pathogenesis of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease is not well understood. This study investigated the roles and regulation of the claudin-1, -2, -3, and -4 isoforms in the pathogenesis of ulcerative colitis, and the potential therapeutic effects of nobiletin. Methods: Colitis was induced in rats by administering dextran sulfate sodium [DSS] in drinking water for seven days. Animals were treated daily with nobiletin [oral, 60 mg/Kg body weight] and studied in four groups, C [non-colitis control], D [DSS-induced colitis], CN [nobiletin-treated non-colitis control], and DN [nobiletin-treated DSS-induced colitis]. On day seven, the animals were sacrificed, and colonic tissues were collected and analyzed. Results: Both macroscopic and microscopic findings suggest the progression of colitis. In the inflamed colon, claudin-1 and -4 proteins were decreased, claudin-2 increased, while the claudin-3 protein remained unchanged. Except for claudin-1, these changes were not paralleled by mRNA expression, indicating a complex regulatory mechanism. Uniform β-actin expression along with consistent quality and yield of total RNA indicated selectivity of these changes. Nobiletin treatment reversed these changes. Conclusions: Altered expression of the claudin isoforms -1, -2, and -4 disrupts tight junctions, exposing the lamina propria to microflora, leading to electrolyte disturbance and the development of ulcerative colitis. Nobiletin with its anti-inflammatory properties may be useful in IBD.