Alteration of the α5 GABA receptor and 5HTT lead to cognitive deficits associated with major depressive-like behaviors in a 14-day combined stress rat model.

INTRODUCTION: Current models used to study the pathophysiology of major depressive disorder (MDD) are laborious and time consuming. This study examined the effect of a 14-day combined stress model (CS; corticosterone injection and restraint stress) in male Sprague-Dawley rats and also compare the effect of CS versus 28-day corticosterone treatment on depressive-like behaviour and cognitive deficits. MATERIEL AND METHODS: Depressive-like behaviours and cognitive deficits were assessed in the forced swim test (FST), sucrose preference (SPT), Morris water maze (MWM) and novel object recognition (NORT) tests. Real-time PCR and ELISA were respectively used to detect expression of the serotonin transporter (5-HTT), serotonin 1 A receptor (5-HT1A), α5 GABAA receptor, and the concentrations of corticosterone (plasma), GABA and acetylcholinesterase (AChE) in the hippocampus and Prefrontal cortex (PFC).Results CS group showed increased immobility time in the FST, time to reach the MWM platform, higher corticosterone level, and increased expressions of hippocampal and PFC 5-HT1A and α5 GABAA receptors, and AChE compared to their control groups. In contrast, reductions in SPT ratio, discrimination index in NORT, time in target quadrant, and hippocampal 5-HTT expression was noted relative to their control group. Compared to the 28-day corticosterone only group, PFC 5-HT1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABAA receptors, and AChE concentrations were higher in the CS group. CONCLUSION: Our CS model induced depressive-like behaviour with early cognitive deficits in rats affecting both hippocampus and PFC. The CS model may be useful in investigating new and comprehensive treatment strategies for MDD.

Trauma-like exposure alters neuronal apoptosis, Bin1, Fkbp5 and NR2B expression in an amyloid-beta (1-42) rat model of Alzheimer's disease.

Post-traumatic stress disorder (PTSD) is a risk factor in the development and progression of Alzheimer's disease (AD), with unclear underlying mechanisms. Recently, we provided data showing the effect of trauma-like stress on Bin1 and Fkbp5 expression in the prefrontal cortex of Aß(1-42) lesioned animals. This present work sought to expand the study by examining the involvement of the amygdala and hippocampus, in addition to highlighting the role of NR2B in the co-occurrence of trauma-like stress and an Aß AD-like pathology. Trauma-like condition was induced by exposing the animals to footshocks. Aß(1-42) was injected into the hippocampus of the animals to induce AD-like pathology. Cognitive functions were assessed in the Morris water maze (MWM) and novel object recognition tests, after which amygdala and hippocampus tissues were harvested for neurochemical analyses. We found that the combination of footshocks and Aß(1-42) lesion caused a decrease in the number of crossings in the target quadrant of the Morris water maze test, indicating memory deficits. Footshocks caused a further downregulation of Bin1 in the amygdala of Aß(1-42)-lesioned rats. Prior exposure to footshocks downregulated NR2B in the hippocampus of Aß(1-42)-lesioned rats. In addition, a combination of footshocks and Aß(1-42) lesion sustained the upregulation of Fkbp5 in the hippocampus and amygdala. A combination of footshocks and Aß(1-42) lesion increased neuronal apoptosis in the hippocampus and amygdala. In conclusion, exposure to a trauma-like condition may influence AD-like pathology, leading to exaggerated behavioural and molecular changes in the amygdala and hippocampus.

Effects of combination antiretroviral drugs (cART) on hippocampal neuroplasticity in female mice.

The incidence of HIV-associated neurocognitive disorder (HAND) continues despite the introduction of combination antiretroviral drugs (cART). Several studies have reported the neurotoxicity of individual antiretroviral drugs (monotherapy), while the common approach for HIV treatment is through cART. Hence, the current study investigated the effects of long-term exposure to cART on cognitive function, oxidative damage, autophagy, and neuroplasticity in the hippocampus of mice. Female Balb/c mice received a once-a-day oral dose of cART composed of emtricitabine + tenofovir disoproxil fumarate or vehicle for 8 weeks. On week 7 of drug administration, all mice were assessed for spatial learning in the Morris water maze (MWM), and then on week 8, mice were sacrificed, and hippocampal tissue dissected from the brain. For biochemical analyses, we measured the concentration of 4-hydroxynonenal, and the expression of autophagic marker LC3B, synaptophysin, and brain-derived neurotrophic factor (BDNF) in the hippocampus. Our results showed that cART exposure increased escape latency in the MWM test. The cART-treated mice also showed increased 4-hydroxynonenal concentration and expression of LC3B. Furthermore, cART treatment decreased the expression of synaptophysin and BDNF. These findings further support the evidence that cART may be neurotoxic and therefore may play a role in the neuropathogenesis of HAND.

Memory decline correlates with increased plasma cytokines in amyloid-beta (1-42) rat model of Alzheimer's disease.

Dysregulation of inflammatory markers like cytokines is implicated in the pathophysiology of Alzheimer's disease (AD). Altered level of these cytokines show that pathogenesis of AD is beyond dysfunction of neurons resulting from amyloid beta accumulation but involves neuroinflammatory mechanisms elicited by the neuroimmune cell. In this study, we investigated the effect of amyloid-beta (1-42) (Aß(1-42)) on memory and how inflammatory markers respond to this model of AD. Male Sprague-Dawley rats were used for this study. The animals were randomly divided into four groups euthanized on day 3, 7, 10 and 14 post-lesion with amyloid-beta (5 µg/5 µl) while corresponding control groups were stereotaxically injected with a vehicle (5 µl of 0.01 M phosphate- buffered saline). The Morris water maze (MWM) test to access learning and memory was conducted pre and post-lesion and blood was collected through cardiac puncture on day 3, 7, 10 and 14 post lesion. Multiplex immunoassay was performed to determine the plasma levels of IL-1ß, IL-6, IL-10 and TNF-α. Our results showed impaired spatial memory and elevated plasma levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) with a concomitantly lowered level of the anti-inflammatory cytokine (IL-10) in the Aß(1-42) lesioned rats when compared to the vehicle groups. This study showed a negative correlation between the decline in performance of the spatial memory task and plasma levels of the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α and positive correlation with the anti-inflammatory cytokine IL-10. In conclusion, this study most importantly demonstrated an association between progressive decline in spatial memory and increased plasma cytokine level induced by the infusion of Aß(1-42).

Effects of bromelain on motor responses following intra-medial forebrain bundle 6-OHDA injection in rat model of parkinsonism.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The conventional therapeutic measures which include the widely used L-DOPA therapy, are inefficient especially when dopamine loss is severe, and the physical symptoms are full blown. Since neuroinflammation is a core feature of PD, this raised the question of whether early treatment with an anti-inflammatory agent may provide a more efficient intervention for PD. In this study, we investigated the effect of bromelain (an anti-inflammatory drug) on motor responses and dopamine levels in a parkinsonian rat model. Male Sprague-Dawley rats were lesioned stereotaxically with the neurotoxin 6-OHDA. The anti-inflammatory agent, bromelain (40 mg/kg i.p) was used to treat a subset of the rats prior to or 24 h post 6-OHDA lesion. Locomotor activity was assessed after 6-OHDA injection, using the cylinder and step tests. The cortical and striatal concentrations of dopamine were also measured. 6-OHDA injection resulted in marked motor impairment which was prevented by pretreatment with bromelain prior to the lesion. Also, the injection of 6-OHDA into the medial forebrain bundle resulted in a significant reduction in dopamine concentration in the striatum and PFC. Bromelain treatment did not alter the suppression of cortical and striatal dopamine levels. Pre-treatment with bromelain reduced the motor dysfunction in the parkinsonian rat model of PD. The efficacy of treatment with bromelain does not appear to be via preservation of the dopaminergic system. The efficacy of bromelain in 6-OHDA injected rats still remains unclear.

Triterpene derivative improves the renal function of streptozotocin-induced diabetic rats: a follow-up study on maslinic acid.

Introduction: Reports indicate that oral administration of plant-derived maslinic acid (MA) exhibits hypoglycemic and renoprotective effects in streptozotocin (STZ)-induced diabetic rats. Challenges with triterpenes such as MA include low bioavailabilty which affects treatment efficacy in experimental animals. The goal of this study was to synthesize the MA derivative phenylhydrazine (PH-MA) in an effort to improve the efficacy of MA. Methods: Separate groups of non-diabetic and STZ-induced diabetic rats (n = 6) were anesthetized and the jugular vein cannulated for the infusion of 0.077 M NaCl at 9 mL/h. The bladder was catheterized for collection the urine samples every 30 min. After 30.5 h equilibration period, consecutive 30 min urine collections were made over the subsequent 4 h of 1 h control, 1.5 h treatment, and 1.5 h recovery periods. PH-MA (22 µg/h) and MA (90 µg/h) were added during the treatment periods for analysis of proximal tubular Na+ handling, plasma aldosterone and arginine vasopressin in male Sprague-Dawley rats. Results: Intravenous infusion of PH-MA (22 µg/h) and MA (90 µg/h) significantly (p Ë‚ .05) increased Na+ output, fractional excretion of Na+ (FENa) and lithium (FELi). Interestingly, like MA, PH-MA significantly (p Ë‚ .05) increased glomerular filtration rate (GFR) over the treatment period and decreased plasma aldosterone levels. Our findings indicate that PH-MA inhibited sodium reabsorption in the proximal and distal tubule as shown by increased FENa and low plasma aldosterone levels, respectively. Conclusions: PH-MA is, therefore, a promising multitarget antidiabetic agent that may ameliorate kidney function of diabetic patients at a dose four times lower than the parent compound (MA).

The pectin-insulin patch application prevents the onset of peripheral neuropathy-like symptoms in streptozotocin-induced diabetic rats.

Peripheral neuropathic condition is amongst the classical symptoms of progressed diabetes. An intensive glycemic control with insulin injections has been shown to delay the onset and the progression of this condition in diabetes. In this study, we investigated the effect of pectin-insulin patch application on peripheral neuropathic symptoms in streptozotocin-induced diabetic rats. Pectin-insulin patches (20.0, 40.8, and 82.9 µg/kg) were daily applied thrice in streptozotocin-induced diabetic rats for 45 days. The diabetic animals sham treated with insulin-free patch served as negative control, while diabetic animals receiving subcutaneous insulin served as positive controls. The locomotor activity, gripping strength, and thermal perception were assessed at day 36, day 40, and day 44, respectively. On the 45th day, the animals were sacrificed, after which the plasma insulin, nitric oxide, C-reactive protein, tumor necrosis factor alpha, and malondialdehyde were measured. The patch application attenuated hyperglycemia with an improvement in the locomotor activity, thermal perception, and gripping strength in diabetic animals. Furthermore, the application of the patch augmented plasma nitric oxide while attenuating plasma malondialdehyde and tumor necrosis factor alpha. The application of pectin-insulin patch delays the onset of peripheral neuropathic-like symptoms in diabetic animals.

Epigenetics: a link between addiction and social environment.

The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.

The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats.

Human immunodeficiency virus type 1 (HIV-1) affects the central nervous system (CNS) that may lead to the development of HIV-associated neuropathologies. Tat protein is one of the viral proteins that have been linked to the neurotoxic effects of HIV. Since many individuals living with HIV often experience significant adverse circumstances, the present study investigated whether exposure to stressful conditions would exacerbate harmful effects of tat protein on brain function. Tat protein (10 µg/10 µl) was injected bilaterally into the dorsal hippocampus of the animal using stereotaxic techniques. The control group received an injection of saline (10 µl). Some control and tat protein-treated animals were subjected to restrain stress for 6 h per day for 28 days and compared to a non-stress group. All animals underwent two behavioural tests, the open field test (OFT) and the novel object recognition test (NORT) to assess their mood state and cognitive function respectively. The release of pro-inflammatory cytokines (TNF-α and IL-1ß) and the expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were also measured to see whether the impact of the repetitive stress on Tat protein-induced behavioural effects was mediated by elements of the immune system and the HPA axis. Rats treated with tat protein showed the following behavioural changes when compared to control animals: there was a significant decrease in time spent in the center of the open field during the OFT, a significant reduction in time spent with the novel object during the NORT, but no change in locomotor activity. Real-time PCR data showed that the expression levels of GR and MR mRNA were significantly reduced, while Western blot analysis showed that the protein expression levels of TNF-α and IL-1ß were significantly increased. The present findings indicated that injection of tat protein into the hippocampus of rats not subjected to stress may lead to anxiety-like behaviour and deficits in learning and memory. Tat-treated animals subjected to stress evoked only a modest effect on their behaviour and neurochemistry, while stress alone led to behavioural and neurochemical changes similar to tat protein.

Differential epigenetic changes in the hippocampus and prefrontal cortex of female mice that had free access to cocaine.

Alterations in gene expression within the neural networks of prefrontal cortex (PFC) and hippocampus (HPC) are known to contribute to behavioural phenotypes associated with drug intake. However, the functional consequences of regulated expression patterns of Fosb and Crem (cAMP response element modulator) in both brain regions in response to volitional intake of cocaine in social environment is yet to be explored. Here, we first exposed young adult mice to cocaine (300 mg/L) and water concurrently for 30 days in the IntelliCage to investigate consumption preference, and subsequently for 28 days during which persistent motivated drug seeking behaviours were examined. Thereafter, locomotor activity and memory performance of the mice were assessed. DNA methylation status in the promoters of Fosb and Crem genes were also evaluated. We show that mice that had extended access to cocaine exhibited motivational deficit and demonstrated decreased locomotor activity and intact recognition memory. These changes were accompanied by hypomethylation or hypermethylation in the promoters of Fosb and Crem genes in the PFC and HPC of the cocaine-experienced mice, respectively. Together, these findings correlate the molecular changes to behavioural effects of the treatment and further suggests a possible activation of prefrontal cortical networks by social interaction episodes in the IntelliCage which possibly enhanced behavioural control that dampens mice sensitivity to cocaine rewards. Furthermore, our data delineate the molecular response of Crem and Fosb to oral cocaine in group-housed mice and demonstrates differential regulation of activities within the substrate brain regions studied.

The Ameliorative Effect of Pectin-Insulin Patch On Renal Injury in Streptozotocin-Induced Diabetic Rats.

BACKGROUND/AIMS: Renal damage and dysfunction is attributed to sustained hyperglycaemia in overt diabetes. Subcutaneous insulin injections are beneficial in delaying the progression of renal dysfunction and damage in diabetics. However, the current mode of administration is associated with severe undesirable effects. In this study, we evaluated the ameliorative effects of pectin-insulin dermal patches on renal dysfunction in diabetes. METHODS: Pectin-insulin patches (20.0, 40.8 and 82.9 µg/kg) were applied on the skin of streptozotocin-induced diabetic rats, thrice daily for 5 weeks. Blood glucose concentration, blood pressure and urine output volume were recorded on week 5 after which the animals were sacrificed after which the kidneys and plasma were collected. Kidney nephrin expression and urinary nephrin concentration, albumin excretion rate (AER), creatinine clearance (CC) and albumin creatinine ratio (ACR) were assessed. RESULTS: Patch application resulted in reduced blood glucose concentration and blood pressure. Furthermore, pectin-insulin patch treatment resulted in increased kidney nephrin expression and reduced urinary nephrin concentration. AER, CC ACR were also reduced post patch application. CONCLUSIONS: The application of pectin-insulin patch limited diabetes associated kidney damaged and improved kidney function. These observations suggest that pectin-insulin patches may ameliorate kidney dysfunction that is associated with chronic subcutaneous insulin administration.

Post 6-OHDA lesion exposure to stress affects neurotrophic factor expression and aggravates motor impairment.

Chronic exposure to stress amplifies locomotor deficits and exacerbates dopamine neuron loss in an animal model for Parkinson's disease. The release of neurotrophic factors such as glial cell-line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) following neuronal injury attenuates exacerbated degeneration of these neurons. In this study, the neurotoxin 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle of male Sprague Dawley rats. A subset of these rats was subjected to post-lesion restraint stress after which the effect of exposure to stress on locomotor activity (forelimb akinesia test), neurotrophic factor (GDNF and NT-3) and corticosterone concentration was assessed. Exposure to post-lesion stress resulted in increased preference to use the unimpaired forelimb (forelimb ipsilateral to the lesioned hemisphere) in the forelimb akinesia test. The expected increase in both GDNF and NT-3 concentration following injury was not present in the stressed animals. However, both the non-stressed and stressed lesioned groups had decreased neurotrophic factor concentration at one and two weeks post lesion. This decrease was exaggerated in the stressed rats. The decrease in neurotrophic factor concentration was accompanied by an increase in corticosterone concentration in the stressed rats. These findings demonstrate that exposure to post-6-OHDA lesion stress exaggerates dopamine neurodegeneration and enhance motor impairment. This suggests that conditions that result in a hyper-activated hypothalamic-pituitary-adrenal axis such as depression which is concomitant to a Parkinson's disease diagnosis may be responsible for enhanced dopamine depletion by attenuating neurotrophic factor concentration elevation in the nigrostriatal pathway following neuronal injury.

Pre-infection administration of asiatic acid retards parasitaemia induction in Plasmodium berghei murine malaria infected Sprague-Dawley rats.

BACKGROUND: Malaria prevention has remained a critical area in the absence of efficacious vaccines against malaria. Drugs currently used as chemotherapeutics are also used in chemoprophylaxis increasing possible drug resistance. Asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties with emerging anti-malarial potential. The influence of asiatic acid administration prior to Plasmodium berghei infection of Sprague-Dawley rats on parasitaemia induction is here reported. METHODS: Sprague-Dawley rats (90-120 g) were administered with asiatic acid (10 mg/kg) 48 h before intraperitoneal infection with P. berghei. Parasitaemia induction and progression, food and water intake as well as weight were compared to 30 mg/kg chloroquine-treated and infected control rats during sub-chronic studies (21 days). RESULTS: Asiatic acid pre-infection administration preserved food and water intake as well as increase in percentage weight gain of infected animals. In pre-infection treated animals, the pre-patent period was extended to day 6 from 72 h. Asiatic acid suppressed parasitaemia while oral chloroquine (30 mg/kg) did not influence malaria induction. CONCLUSIONS: Per-oral, pre-infection, asiatic acid administration influenced parasitaemia patency and parasitaemia progression, food, water, and weight gain percentage. This may suggest possible chemoprophylaxis effects of asiatic acid in malaria.

Prenatal stress and early life febrile convulsions compromise hippocampal genes MeCP2/REST function in mid-adolescent life of Sprague-Dawley rats.

Early life neuronal insults exacerbate the development of febrile seizures and can result in epigenetic changes in the hippocampus. The MeCP2 and REST genes play a pivotal role in cognition as both contribute to neuronal function. In this study, cognitive function and expression of the MeCP2 and REST genes in the hippocampus were investigated in four groups of Sprague Dawley rats offspring viz. (1) Normally reared treated with saline (NSS). (2) Prenatally stressed treated with saline (SS). (3) Normally reared with febrile seizures (NSFS). (4) Prenatally stressed with febrile seizures (SFS). Pregnant dams were subjected to 1h of restraint stress for 7days starting on gestational day 14. Following birth, a once-off exposure to saline injections or febrile seizure induction was conducted on postnatal day (PND) 14. Behavioural tests were conducted using the Morris-Water maze on PND 21 and 30. Our results showed a febrile seizure effect on learning and memory in the non-stressed animals. However, febrile seizures did not exacerbate learning deficits in the prenatally stressed animals. Gene analysis found a down-regulation in MeCP2 gene expression and an up-regulation of the REST gene in prenatally stressed animals. Exposure to febrile seizure resulted in down-regulation of both MeCP2 and REST gene expression in the non-stressed animals, but febrile seizures did not exacerbate the stress effect on gene expression. This suggests that exposure to prenatal stress (SS) and febrile seizures (NSFS) may impair cognitive behavioural function. However, in the NSFS animals, there seems to be an attempt to counteract the effects of febrile seizures with time.

The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rats following 6-hydroxydopamine-induced neuronal insult.

Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5 mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p < 0.05), when compared to controls. In contrast, brain iron levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p < 0.05). Following 6-OHDA exposure, the levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p < 0.05). Prenatal MeHg exposure further increased these trace element levels thereby promoting toxicity (p < 0.05). Total antioxidant capacity was not significantly different in MeHg and control groups prior to lesion. However, following 6-OHDA administration, MeHg-exposed animals had a significantly lower TAC than that of controls (p < 0.05). Brain TAC levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood.

The interaction between stress and exercise, and its impact on brain function.

In response to acute adversity, emotional signals shift the body into a state that permits rapid detection, identification, and appropriate response to a potential threat. The stress response involves the release of a variety of substances, including neurotransmitters, neurotrophic factors, hormones, and cytokines, that enable the body to deal with the challenges of daily life. The subsequent activation of various physiological systems can be both protective and damaging to the individual, depending on timing, intensity, and duration of the stressor. Successful recovery from stressful challenges during early life leads to strengthening of synaptic connections in health-promoting neural networks and reduced vulnerability to subsequent stressors that can be protective in later life. In contrast, chronic intense uncontrollable stress can be pathogenic and lead to disorders such as depression, anxiety, hypertension, Alzheimer's disease, Parkinson's disease, and an increased toxic response to additional stressors such as traumatic brain injury and stroke. This review briefly explores the interaction between stress experienced at different stages of development and exercise later in life.

Effects of combined postweaning social isolation and ketamine administration on schizophrenia-like behaviour in male Sprague Dawley rats.

The pathophysiology behind negative and cognitive symptoms of schizophrenia is not well understood, thus limiting the effectiveness of treatment on these symptoms. Developing reliable animal model of schizophrenia is vital to advance our understanding on the neurobiological basis of the disorder. Double hit is used to refer to the use of two schizophrenia inducing interventions viz ketamine exposure and social isolation. In this study we aim to investigate the robustness of double hit model of schizophrenia in inducing negative and cognitive symptoms of schizophrenia. On postnatal day (PND) 23, thirty-two male Sprague Dawley rats were randomly grouped into four equal groups as follows: group housed + saline (GH), group housed + ketamine (GHK), isolated + saline (SI), and isolated + ketamine (SIK). A single ketamine dose (16mg/kg) was administered 3 times a week for four weeks. Isolated animals were housed singly throughout the study. The following behavioural tests were carried out: elevated plus maze, three chamber social interaction, resident intruder tests, and novel object recognition (NOR). The SIK group exhibited high anxiety levels, with increased ACTH, corticosterone and norepinephrine concentration when compared to the other groups. The SIK animals also presented with reduced social interaction and decreased oxytocin concentration. SIK rats were more aggressive towards a juvenile intruder but had low testosterone concentration. The SIK group or double hit model showed impaired visual learning and memory and increased expression of proinflammatory cytokines. This suggest that the double hit model is more robust in inducing negative and cognitive symptoms of schizophrenia than each treatment alone.

Global perspectives on the traditional approaches used in the treatment of schizophrenia: A systematic review.

BACKGROUND: Traditional healing considers a holistic approach when diagnosing and treating patients for mental ailments, and is the preferred approach globally. OBJECTIVE: This review documented traditional healing approaches for treatment of schizophrenia used in different regions globally. METHODS: PICO framework was used to facilitate literature search from Google Scholar, PubMed, Medline, Cochrane, Scopus, APA PsycINFO, and Web search. Studies documenting methods of treatment from the perspective of traditional healers, patients and/or caregivers were included and also studies which investigated herbal plants used in traditional healing in vitro and in vivo were included. Review articles, magazine/newspaper articles, editorials, letters, comments/opinion articles, and articles with inaccessible full text were excluded. The risk of bias was assessed using MMAT and SYRCLE tools. University Capacity Development Programme funded this review. RESULTS: 74 articles were included, these documented traditional healing practices used in Africa, Asia, America, Europe, and Oceania. Common approach globally was herbal medicine. Other reported methods included faith-based healing, consultation with the ancestors, performing rituals, acupuncture, and music and yoga therapies. Inhumane approaches included starving, beating, cutting and confining patients. In some cases, traditional healing was used as adjunctive treatment. The overall risk of bias for studies in this review was low. CONCLUSION: Traditional healing contributes in bridging the treatment gap for schizophrenia in developing countries. However, there is a lack of standardisation of the approaches employed in the different regions, and the safety and effectiveness of some of these approaches remain questionable.

The antipsychotic potential of Salix Mucronata on ketamine-induced rats.

Salix mucronata is one of the herbal plants offered by the traditional health practitioners in KwaZulu-Natal, South Africa for the treatment of schizophrenia. This study aimed to investigate the effects of repeated administration of ketamine on social interaction, novelty and motivation in adult, male Sprague Dawley rats. It also aimed to investigate the potential of risperidone and the herbal extract of S. mucronata to reverse impairments that are induced by ketamine. Experimental rats (n=45) received a dose of ketamine at 30 mg/kg via intraperitoneal injection for 5 consecutive days. They were then allocated into their respective treatment groups and given risperidone (APD) and the herbal extract of S. mucronata (TM) at doses of 6 mg/kg and 5 mg/kg, respectively, for 7 consecutive days. Social behaviour was tested using the 3-chambered sociability test, and anhedonia was tested using the sucrose preference test. Ketamine induction elicited social withdrawal and reduced social novelty which were later successfully reversed by risperidone and S. mucronata. The rats showed reduced preference to sucrose post-induction and post-treatment. Ketamine and mild stress caused by scruff restraint elicited reduced weight gain for the animals. No differences were noted on brain mass between controls and experimental groups and also between risperidone and S. mucronata groups. However, reduced brain volume was noted in experimental groups. Dopamine and acetylcholine concentration levels were high in groups which received risperidone and S. mucronata. These findings highlight that the antipsychotic potential of S. mucronata is similar to risperidone.

Investigating the Robustness of a Rodent "Double Hit" (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review.

Schizophrenia is a debilitating psychiatric disorder comprising positive, negative, and cognitive impairments. Most of the animal models developed to understand the neurobiology and mechanism of schizophrenia do not produce all the symptoms of the disease. Therefore, researchers need to develop new animal models with greater translational reliability, and the ability to produce most if not all symptoms of schizophrenia. This review aimed to evaluate the effectiveness of the rodent "double hit" (post-weaning social isolation and N-methyl-D-aspartate (NMDA) receptor antagonist) model to produce symptoms of schizophrenia. This systematic review was developed according to the 2020 PRISMA guidelines and checklist. The MEDLINE (PubMed) and Ebscohost databases were used to search for studies. The systematic review is based on quantitative animal studies. Studies in languages other than English that could be translated sufficiently using Google translate were also included. Data extraction was performed individually by two independent reviewers and discrepancies between them were resolved by a third reviewer. SYRCLE's risk-of-bias tool was used to test the quality and biases of included studies. Our primary search yielded a total of 47 articles, through different study selection processes. Seventeen articles met the inclusion criteria for this systematic review. Ten of the seventeen studies found that the "double hit" model was more effective in developing various symptoms of schizophrenia. Most studies showed that the "double hit" model is robust and capable of inducing cognitive impairments and positive symptoms of schizophrenia.