Optimization of Parkinson's disease therapy with plant extracts and nutrition's evolving roles.

Parkinson's disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Death of dopaminergic cells in the SNpc leads to manifestations of motor dysfunction and non-motor symptoms of PD. The progression of PD symptoms severely affects the quality of life of patients and poses socio-economic problems to families and society at large. The clinical and neuropathological characteristics of PD are triggered by multiple factors such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation. Notwithstanding the advancements in pharmacological therapy in PD management, there is burgeoning interest in alternative and complementary approaches, essentially nutrition and plant extracts strategies. This review gives widespread analysis of the role of nutrition and plant extracts in the management of PD. Studies that investigated the effects of various dietary compounds and plant extract on PD symptoms and progression were reviewed from existing literatures. Nutraceuticals, including vitamins and phytochemicals such as Mucuna pruriens have shown potential neuroprotective functions in preclinical and clinical studies. Indeed, these strategies ameliorate mitochondrial dysfunction, oxidative stress, and neuroinflammation, all which are implicated in the pathogenesis of PD. The neuroprotective mechanisms of nutrition and plant extracts in PD, with emphasis on their capacity to target multiple pathways implicated in PD are discussed. Additionally, challenges and limitations related with translating preclinical findings into clinical practice including standardization of dosing regimens, bioavailability, and inter-individual variability are discussed. Largely, this review elucidates on the role of nutrition and plant extracts as adjunctive therapy in PD management.

Comparative study of antipyretic potency of extracts of morinda lucida leaves and fruits of capsicum frutescens in albino rats.

Background: Morinda lucida leaves and fruits of Capsicum frutescens are used locally in the management of fever in Nigeria. No scientific credence has been lent to this claim. Objective: To investigate the antipyretic effect and potency of aqueous extracts of Morinda lucida leaves and fruits of Capsicum frutescens in albino rats. Method: Brewer's yeast was used to induce pyrexia. Thirty animals were divided into six groups. Group A was orally administered normal saline (103 mg/kg). Group B was served indomethacin (5 mg/kg), while groups C and D received aqueous extract of Capsicum frutescens at 100mg/kg and 200mg/kg, 17 hours post induction of pyrexia. Groups E and F were administered extract of Morinda lucida at the same doses. Rectal temperature of the animals was taken at 60-, 90- and 120-minutes post-treatment. Results: Both C. frutescens and M. lucida produced significant reduction (p<0.05) in rectal temperature after 120 minutes in the rats compared with animals in the control group. Also, the antipyretic activities of the two extracts at 100mg/kg and 200mg/kg were comparable to 5mg/kg of indomethacin, with apparent dose dependence in the antipyretic activities of both extracts. Conclusion: Morinda lucida leaves and fruits of Capsicum frutescens exhibit dose-dependent antipyretic activities.

Neuroinflammation and microglial expression in brains of social-isolation rearing model of schizophrenia.

Schizophrenia is a psychiatric disorder with a global prevalence of approximately 0.45%. It is considered a mental illness, with negative symptoms, positive symptoms, and cognitive dysfunction. The outcomes of studies on the role of microglia and neuroinflammation have been conflicting. In addition, there is a poor understanding of the sex differences in microglial expression and neuroinflammation markers in the prefrontal cortex, hippocampus, and nucleus accumbens. Understanding the exact roles of neuroinflammation may guide the development of efficient therapeutic drugs that can address the negative, positive, and cognitive symptoms of the disease. We examined the effect of social isolation rearing on schizophrenia-related behaviours in male and female BALB/c mice. The social-isolation rearing protocol started on post-natal day (PND) 21, lasting for 35 days. Animals were assigned to four cohorts, consisting of five animals per group. On PND 56, animals were assessed for behavioural changes. We used enzyme-linked immunosorbent assays to investigate the expression of nuclear factor kappa B (NF-κB), tumour necrosis factor-α (TNF-α), and Interleukin-1ß (IL-1ß) in the hippocampus, nucleus accumbens, and prefrontal cortex. Immunohistochemistry was used to assess the expression of microglia in the three brain regions. Our study showed that isolation rearing led to increasing locomotion, heightened anxiety, depression, and a reduced percentage of prepulse inhibition. There was a significant increase (p < 0.05) in anxiety in the female isolation mice compared to male isolation mice. Furthermore, isolation rearing significantly increased microglia count (p < 0.05) in the hippocampus, nucleus accumbens, and prefrontal cortex, only in the male group. There was microglial hyper-activation as evident in the downregulation of CX3CR1 in both male and female social-isolation groups. Male social-isolation mice showed a significant increase (p < 0.05) in neuroinflammation markers only in the nucleus accumbens while the female social-isolation mice showed a significant increase (p < 0.05) in neuroinflammation markers in both the nucleus accumbens and hippocampus. The study showed that therapeutic interventions aimed at modulating CX3CR1 activity and reducing inflammation may be beneficial for patients with schizophrenia.

Effect Of Caffeine and Adrenaline on Memory and Anxiety in Male Wistar Rats.

The present study was designed to investigate the effects of caffeine and adrenaline administration on memory and anxiety in male rats. Rats weighing about 140-200g were used for the study. They were divided into three groups (4 animals per group). Study groups 1; a,b,c,d were healthy rats administered normal saline, 5,10 and 15mg/kg bw caffeine intraperitoneally (i.p.), respectively for 6 weeks. Study groups 2; a,b,c,d administered normal saline, 0.1, 0.2 and 0.31mg/kg bw adrenaline (i.p.), respectively for 6 weeks. Study groups 3; a,b,c,d administered normal saline, 5mg/kg caffeine (i.p.) + 0.1mg/kg adrenaline (i.p.), 10mg/kg Caffeine (i.p.) + 0.2mg/kg Adrenaline (i.p.) and 15mg/kg Caffeine (i.p.) + 0.3mg/kg Adrenaline (i.p.) respectively for 6 weeks. The result showed no significant difference in spatial memory across all animals in study groups 1: b,c,d when compared to control (a). Study groups 2: (b, c) showed increase in spatial memory when compared to control (a). 2(d) showed a significant (p<0.05) decrease. Study groups 3: b, c, d showed no significant difference in spatial memory when compared to control (a). Study groups 1: b, c showed significant (p<0.05) reduction in duration for the short and long term memory test when compared to control. Study groups 2 showed reduction in duration for both the long and short term memory test when compared to control Study groups 3 no significant (p<0.05) difference in short and long term memory test across all animals in the group. It was also observed that adrenaline enhanced short and long term memory and only high dose of adrenaline distorted spatial memory. Study groups 1; (b,c) showed significant (p<0.05) increase in the number of entries to the open arm of the elevated plus maze when compared to control (a). Study groups 2; (b), showed significant (p<0.05) increase in the frequencies of entries to the closed arm of the elevated plus maze when compared to control (a). Study groups 2; (d), showed a significant (p<0.05) decrease in the frequency of entries to the open and closed arm when compared to control (a). The study revealed that co- administration of caffeine and adrenaline led to elevation of mood, increased activity and reduction of anxiety in Wistar rats. In addition, it was observed that only high dose of adrenaline increased anxiety. It was also observed that caffeine and adrenaline enhanced short and long term memory and only high dose of adrenaline distorted spatial memory.

Synergistic interaction between acetaminophen and L-carnosine improved neuropathic pain via NF-κB pathway and antioxidant properties in chronic constriction injury model.

Background: Inflammation is known to underlie the pathogenesis in neuropathic pain. This study investigated the anti-inflammatory and neuroprotective mechanisms involved in antinociceptive effects of co-administration of acetaminophen and L-carnosine in chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. Methods: Fifty-six male Wistar rats were randomly divided into seven experimental groups (n = 8) treated with normal saline/acetaminophen/acetaminophen + L-carnosine. CCI was used to induce neuropathic pain in rats. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests, respectively. Investigation of spinal proinflammatory cytokines and antioxidant system were carried out after twenty-one days of treatment. Results: The results showed that the co-administration of acetaminophen and L-carnosine significantly (P < 0.001) increased the paw withdrawal threshold to thermal and mechanical stimuli in ligated rats compared to the ligated naïve group. There was a significant (P < 0.001) decrease in the levels of nuclear factor kappa light chain enhancer B cell inhibitor, calcium ion, interleukin-1-beta, and tumour necrotic factor-alpha in the spinal cord of the group coadministered with acetaminophen and L-carnosine compared to the ligated control group. Co-administration with acetaminophen and L-carnosine increased the antioxidant enzymatic activities and reduced the lipid peroxidation in the spinal cord. Conclusions: Co-administration of acetaminophen and L-carnosine has anti-inflammatory effects as a mechanism that mediate its antinociceptive effects in CCI-induced peripheral neuropathy in Wistar rat.

Therapeutic effects of crude extracts of Bacopa floribunda on beta-amyloid 1-42-induced Alzheimer's disease via suppression of dyslipidemia, systemic inflammation and oxidative stress in male Wistar Rats.

Aims: Bacopa floribunda (BF), an African traditional plant and its species have been widely used as brain tonic for memory enhancement. It has also been reported to help relieve anxiety and some psychological disorders. This study aimed to investigate the mechanisms of action of BF on Amyloid beta (Aß) 1-42 peptides induced cognitive deficit in male Wistar rats. Main methods: A total of 48 healthy male wistar rats were used for this study. Some groups were pre-treated with 200 mg/kg of BF extracts before a single bilateral injection of Aß 1-42 while some were post-treated with BF for 21 days after Aß1-42 exposure. Cognitive performance was evaluated using Y-Maze and Novel Object recognition tests. After treatments, hippocampal homogenates were assayed for the levels of Acetylcholinesterase, Na-K/ATPase activities, glutamate and Aß1-42 concentrations among others. Key findings: It was observed that Aß1-42 caused cognitive impairment and BF extracts especially the ethanol extract was able to significantly (p < 0.05) reverse almost all the perturbations including lipid imbalance caused by Aß1-42 assault mainly at the post-treatment level. Significance: Administration of ethanol and aqueous extracts of BF mitigated the hazardous effect of Aß1-42 observed in the blood plasma and hippocampal homogenates. In this context, we conclude that BF is an efficient cognitive enhancer that can help alleviate some symptoms associated with Alzheimer's disease.

Chondroitin and glucosamine sulphate reduced proinflammatory molecules in the DRG and improved axonal function of injured sciatic nerve of rats.

Neuropathic pain (NP) is an abnormality resulting from lesion or damage to parts of the somatosensory nervous system. It is linked to defective quality of life and often poorly managed. Due to the limited number of approved drugs, limited efficacy and side effects associated with the approved drugs, drugs or drug combinations with great efficacy and very minimal or no side effects will be of great advantage in managing NP. This study aimed at investigating the synergistic antinociceptive effects of the combination of glucosamine sulphate (GS) (240 mg/kg) and chondroitin sulphate (CS) (900 mg/kg) in chronic constriction injury (CCI)-induced neuropathy in rats. Forty-two Wistar rats were randomly distributed into seven groups (n = 6). Sciatic nerve was ligated with four loose ligatures to induce NP. Effects of drugs were examined on stimulus and non-stimulus evoked potentials, expression of dorsal root ganglia (DRG) pain modulators and structural architecture of DRG. Oral administration of GS and CS for 21 days reduced hyperalgesia, allodynia, sciatic nerve functional aberration and DRG pain modulators. Histopathology and immunohistochemistry revealed restoration of structural integrity of DRG. Our result showed that the combination of GS and CS produced antinociceptive effects by attenuating hyperalgesia, allodynia and downregulation of NP mediators. GS and CS additionally produced synergistic analgesic effect over its individual components.

Saponins and flavonoids from Bacopa floribunda plant extract exhibit antioxidant and anti-inflammatory effects on amyloid beta 1-42-induced Alzheimer's disease in BALB/c mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Bacopa floribunda (BF), a locally available plant has been employed traditionally as memory enhancer in Southwestern, Nigeria. It has been utilized in traditional and Ayurvedic medicine as brain tonic for enhancing memory, anti-aging and forestalling series of psychological disorders. However, there is a dearth of scientific information on the mechanism(s) of action of important phytochemicals from BF extract on dementia. AIM OF THE STUDY: Alzheimer's disease, the commonest form of dementia has been postulated to triple by 2050 as a result of increase in life expectancy. This study therefore assessed and compared the possible mechanism(s) of action of flavonoids and saponins from BF on Amyloid beta (Aß1-42)-induced dementia in male BALB/c mice. MATERIALS AND METHODS: Eighty (80) healthy BALB/c mice divided into 10 groups (n = 8) were given a single bilateral ICV injection of Aß1-42 or normal saline. Graded doses of Saponins and flavonoids (50, 100 and 200 mg/kg) were used as treatment for 21 days. Hippocampal homogenates were assayed for the levels of antioxidants, oxidative stress and neuroinflammatory markers. In vitro antioxidant activity of flavonoids and saponins were equally assessed using standard procedures. The extent of microglial activation was quantified through immunohistochemistry procedure. RESULTS: Aß1-42 successfully caused a spike in hippocampal levels of MDA, IL1ß, TNF-α including MPO levels and invariably decreased antioxidant activities. Likewise an increase in reactive microglia (microgliosis) was observed. However, crude saponins and flavonoids from BF were able to suppress microgliosis, oxidative stress and neuroinflammation induced by Aß1- 42 and were observed to be more effective at higher doses of saponins (100 mg/kg and 200 mg/kg) and flavonoid (100 mg/kg). CONCLUSIONS: Phytochemicals from BF efficiently exhibited dose dependent alleviation of some symptoms associated with Alzheimer's disease.

Vitamin D attenuated 6-OHDA-induced behavioural deficits, dopamine dysmetabolism, oxidative stress, and neuro-inflammation in mice.

Background: L-DOPA, the predominant therapy for Parkinson's disease (PD) is associated with motor deficits after prolonged use. The nigrostriatal tract, a primary target of neurodegeneration in PD, contains abundant Vitamin-D receptors, suggesting a potential role for VD in the disease. Therefore, we tested the impact of Vitamin D3 (VD3) in a mouse model of PD.Methods: PD was induced in adult male C57BL6 mice by a single intrastriatal injection of 6-hydroxydopamine. Two weeks post lesion, these mice received injections of a vehicle, VD3, L-DOPA, or a combination of VD3/L-DOPA and compared with sham controls. Treatment lasted three weeks, during which motor-cognitive neurobehaviour was assessed. Five weeks post lesion, brains were collected and striatal levels of the following proteins assessed: tyrosine hydroxylase (TH), dopamine decarboxylase (DDC), monoamine oxidase (MAO-B), Catechol-O-methyl transferase (COMT), dopamine transporter (DAT), brain-derived neurotrophic factor (BDNF), microglia marker (CD11b), inflammation (IL-1ß), apoptotic signaling (BAX) and oxidative stress (p47phox).Results: Treatment with VD3 attenuated behavioural deficits induced by 6-OHDA, protein associated with dopamine metabolism and biomarkers of oxidative stress. VD3 significantly increased contralateral wall touches, exploratory motor and cognitive activities. VD3 significantly enhanced the expression of TH, DAT, BDNF, while significantly reducing expression of MAO-B, CD11b, IL-I ß and p47phox.Conclusion: VD3 reversed some of the 6-OHDA induced changes in proteins involved in modulating the dopamine system, behavioural deficits and oxidative stress biomarkers. The data suggests that VD3 might be beneficial in reducing L-DOPA dosage, thereby reducing problems associated with dosage and prolonged use of L-DOPA in PD management.

Effects of co-administration of vitamin E and lithium chloride on chronic constriction injury-induced neuropathy in male Wistar rats: Focus on antioxidant and anti-inflammatory mechanisms.

OBJECTIVES: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit E, which may be complementary to the antinociceptive effects of the two substances. METHODS: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight were randomly assigned to 6 experimental groups and administered with normal saline, Vit E, LiCl, or their combination, once daily for 21 days. CCI was used to induce neuropathic pain (NP) and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behavior. Biochemical parameters were assessed in the dorsal root ganglion after 21 days of treatment. RESULTS: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit E synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit E or LiCl. Combined doses of Vit E and LiCl significantly increases the explorative behavior in the OFM. CCI increased malondialdehyde (MDA), tumor necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide, calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit E significantly reduced MDA, TNF-α, but increased SOD compared with ligated control. DISCUSSION: The findings revealed that the synergistic effects of the co-administration of Vit E and LiCl in ameliorating NP are mediated by their anti-inflammatory and antioxidant properties.

Selenium reduces nociceptive response in acute 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity.

The potential of Se to alleviate pain associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity was investigated. Swiss mice were intraperitoneally injected with MPTP (20 mg/kg) 4 times with an interval of 2 h in 1 day. Seven days after MPTP injection, the mice (n = 5 mice per group) were randomly assigned to groups: MPTP-, DOPA (50 mg/kg)-, Se4 (0.4 mg/kg)-, Se6 (0.6 mg/kg)-, DOPA+Se4-, and DOPA+Se6-treated groups were compared with controls. MPTP mice were treated for seven days; thereafter, motor-coordination and nociceptive-motor reactions were assessed. Pro-inflammatory cytokines (IL-1ß, IL-6 and TNFα), and selected pain biomarkers (substance P (SP), glutamate and ß-endorphin) were assessed in the serum and the substantial nigra pars compacta (SNpc). Motor activity was increased slightly by Se (0.6 or 0.4 mg/kg) vs. MPTP (10.48 ± 2.71 or 11.81 ± 1.28 s vs. 3.53 ± 0.06 s respectively) but considerably increased by DOPA (50 mg/kg) vs. MPTP (50.47 ± 3.06 s vs. 3.53 ± 0.06 s respectively). Se and DOPA increased nociceptive threshold but Se alone reduced both serum and SN pro-inflammatory cytokines. Se modulates SP while DOPA modulates SP and glutamate in the SNpc of mice treated with MPTP. Se suppressed pro-inflammatory cytokines and restored the basal pain biomarkers in the SNpc of mice treated with MPTP. Se requires further study as analgesic adjuvant.

Cholecalciferol (VD3) Attenuates L-DOPA-Induced Dyskinesia in Parkinsonian Mice Via Modulation of Microglia and Oxido-Inflammatory Mechanisms.

L-DOPA, the gold standard for managing Parkinson's disease (PD) is fraught by motor fluctuations termed L-Dopa-Induced Dyskinesia (LID). LID has very few therapeutic options. Hence, the need for preclinical screening of new interventions. Cholecalciferol (VD3) treatment reportedly improves motor deficit in experimental Parkinsonism. Therefore, the novel anti-dyskinetic effect of VD3 and its underlying mechanisms in LID was investigated. Dyskinesia was induced by chronic L-DOPA administration in parkinsonian (6-OHDA- lesioned) mice. The experimental groups: Control, Dyskinesia, Dyskinesia/VD3, and Dyskinesia/Amantadine were challenged with L-DOPA to determine the abnormal involuntary movements (AIMs) score during 14 days of VD3 (30 mg/kg) or Amantadine (40 mg/kg) treatment. Behavioral Axial, Limb & Orolingual (ALO) AIMs were scored for 1 min at every 20 mins interval, over a duration of 100 mins on days 1,3,7,11 and 14. Using western blot, striatum was assessed for expression of dopamine metabolic enzymes: Tyrosine Hydroxylase (TH) and Monoamine Oxidase-B (MAO-B); CD11b, BAX, P47phox, and IL-1ß. Cholecalciferol significantly attenuated AIMs only on days 11 & 14 with maximal reduction of 32.7%. Expression of TH and MAO-B was not altered in VD3 compared with dyskinetic mice. VD3 significantly inhibited oxidative stress (P47phox), apoptosis (BAX), inflammation (IL-1ß) and microglial activation (CD11b). VD3 showed anti-dyskinetic effects behaviorally by attenuating abnormal involuntary movements, modulation of striatal oxidative stress, microglial responses, inflammation, and apoptotic signaling; without affecting dopamine metabolic enzymes. Its use in the management of dyskinesia is promising. More studies are required to further evaluate these findings. Keywords: Cholecalciferol; L-DOPA-Induced Dyskinesia; Parkinson's Disease; Microglial; Oxidative stress; Inflammation.

Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy.

BACKGROUND: Several animal models are continually being developed to study diabetic complication. Several conflicting regimen for diabetes induction exist in the literature with varying dose strength and regimen for different study interest in diabetes. This study aims to show the effect of high dose streptozotocin (STZ) on the one hand compared with multiple low doses after high fat diet induction on diabetic cardiac autonomic neuropathy (DCAN). METHODOLOGY: Eighty-four Wistar rats were used to demonstrate DCAN induction using 2 approaches one for T1DM (STZ 50mg/kg) and the other for T2DM (HFD for 8 weeks with STZ 25mg/Kg daily for five days). DCAN features were assessed using invasive biomarkers, histology patterns and cardiac nerve densities. RESULTS: Diabetes induction rate was 76% and 89% in T1DM and T2DM model respectively. T1DM group had significant weight loss, reduced c-peptide, and insulin level post induction. The T2DM additionally showed significantly higher total cholesterol and Homeostatic model assessment (HOMA) compared with control. Serum levels of catecholamine, choactase, nerve growth factor and cardiac nerve density confirms development of DCAN. CONCLUSION: High single dose of STZ and HFD with multiple low doses of STZ may be recommended for DCAN study in T1DM and T2DM rat model respectively.

Chondroitin sulfate produces antinociception and neuroprotection in chronic constriction injury-induced neuropathic pain in rats by increasing anti-inflammatory molecules and reducing oxidative stress.

OBJECTIVES: Damage to the peripheral and central nervous system lead to Neuropathic pain (NP) which is a widespread and devitalizing condition. chondroitin sulfate (CS), has been used in managing joint pain and osteoarthritis. In this study, the effectiveness of CS on NP induced by chronic constriction injury (CCI) is examined. METHODS: Thirty Wistar rats were distributed at random into six groups (n = 5). Sciatic nerve ligation was carried out by encircling the nerve with four loose ligatures to induce NP. Allodynia (cold and mechanical) and heat hyperalgesia were assessed using Acetone, von Frey filament and Hot plate tests. CCI induction resulted to NP, prominent from the 3rd day after surgery. Structural architecture of sciatic nerves was evaluated via histological examination of the transverse section of the nerves. RESULTS: Oral administration of CS (600 mg/kg and 900 mg/kg for 21 days) resulted in significant (P < 0.05) inhibition of allodynia (cold and mechanical) and thermal hyperalgesia. Lipid peroxidation, tumor necrosis factor-α (TNF-α), calcitonin gene related peptide (CGRP), C reactive protein (CRP), and oxidative stress were attenuated by CS. CS also improved interleukin (IL)-6, nitric oxide (NO), total antioxidant capacity (TAC). CONCLUSION: These findings suggest that CS attenuates allodynia, and thermal hyperalgesia induced by CCI by downregulating TNF-α, CRP, CGRP, oxidative enzymes, and upregulating IL-6, NO, and TAC. Nociceptive behavioral studies and histological findings showed significant improvement in the CS treated groups compared to CCI rats. These findings are responsible for the beneficial effect of CS in NP.

Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy.

OBJECTIVES: There has been increasing recognition of the significant relationship between the autonomic nervous system and cardiovascular sequel in diabetes mellitus (DM) patients. Diabetic cardiac autonomic neuropathy (DCAN) still poses a treatment challenge in the clinical settings despite several research interventions. This study was designed to investigate the effect of carvedilol on experimentally induced DCAN in type 2 DM rat model. METHODS: DCAN was induced in 42 Wistar rats using high fat diet (HFD) for eight weeks, thereafter streptozotocin (STZ) at 25 mg/kg daily for five days. DCAN features were then assessed using non-invasive time and frequency varying holter electrocardiogram (ECG), invasive biomarkers, cardiac histology and cardiac nerve density. RESULTS: Carvedilol significantly ameliorated the effects of DCAN on noradrenaline (p=0.010) and advanced glycated end products (AGEs) (p<0.0001). Similarly, carvedilol reversed the reduction in levels of antioxidants, sorbitol dehydrogenase (SD) activity (p=0.009) nerve growth factors (p<0.0001) and choline acetyl-transferase (p=0.031) following DCAN induction. Furthermore, heart rate variability (HRV) indices which were also reduced with DCAN induction were also ameliorated by carvedilol. However, carvedilol had no significant effect on cardiac neuronal dystrophy and reduced cardiac nerve densities. CONCLUSIONS: Carvedilol improves physiological HRV indices and biomarkers but not structural lesions. Early detection of DCAN and intervention with carvedilol may prevent progression of autonomic neurologic sequel.

Plasmodium berghei-induced malaria decreases pain sensitivity in mice.

Various types of pain were reported by people with Plasmodium falciparum and were mostly attributed to a symptom of malarial infection. Neural processes of pain sensation during malarial infection and their contributions to malaria-related death are poorly understood. Thus, these form the focus of this study. Swiss mice used for this study were randomly divided into two groups. Animals in the first group (Pb-infected group) were inoculated with Plasmodium berghei to induce malaria whilst the other group (intact group) was not infected. Formalin test was used to assess pain sensitivity in both groups and using various antagonists, the possible mechanism for deviation in pain sensitivity was probed. Also, plasma and brain samples collected from animals in both groups were subjected to biochemical and/or histological studies. The results showed that Pb-infected mice exhibited diminished pain-related behaviours to noxious chemical. The observed parasite-induced analgesia appeared to be synergistically mediated via µ-opioid, α2 and 5HT2A receptors. When varied drugs capable of decreasing pain threshold (pro-nociceptive drugs) were used, the survival rate was not significantly different in the Pb-infected mice. This showed little or no contribution of the pain processing system to malaria-related death. Also, using an anti-CD68 antibody, there was no immunopositive cell in the brain to attribute the observed effects to cerebral malaria. Although in the haematoxylin and eosin-stained tissues, there were mild morphological changes in the motor and anterior cingulate cortices. In conclusion, the pain symptom was remarkably decreased in the animal model for malaria, and thus, the model may not be appropriate for investigating malaria-linked pain as reported in humans. This is the first report showing that at a critical point, the malaria parasite caused pain-relieving effects in Swiss mice.

Bromelain reduced pro-inflammatory mediators as a common pathway that mediate antinociceptive and anti-anxiety effects in sciatic nerve ligated Wistar rats.

The involvement of pro-inflammatory mediators complicates the complex mechanism in neuropathic pain (NP). This study investigated the roles of bromelain against pro-inflammatory mediators as a mechanism that underpins its antinociceptive and anti-anxiety effects in the peripheral model of NP. Sixty-four male Wistar rats randomly divided into eight groups, were used for the study. A chronic constriction injury model of peripheral neuropathy was used to induce NP. Tail-immersion and von Frey filaments tests were used to assess hyperalgesia while open field and elevated plus mazes were used to assess anxiety-like behaviour. NF-кB, iNOS, nitrate, and pro-inflammatory cytokines were investigated in the plasma, sciatic nerve, and brain tissues using ELISA, spectrophotometer, and immunohistochemistry techniques after twenty-one days of treatment. Bromelain significantly (p < 0.05) improved the cardinal signs of NP and inhibited anxiety-like behaviours in ligated Wistar rats. It mitigated the increases in cerebral cortex interleukin (IL) -1ß, IL-6, and PGE2 levels. Bromelain reduced NF-кB, IL-1ß, IL-6, TNF-α, PGE2, and nitrate concentrations as well as the expression of iNOS in the sciatic nerve. Hence, the antinociceptive and anxiolytic effects of bromelain in the sciatic nerve ligation model of NP is in part due to its ability to reduce nitrosative and inflammatory activities.

Antinociceptive effects of lead acetate in sciatic nerve chronic constriction injury model of peripheral neuropathy in male Wistar rats.

The toxicological effects of lead and its compounds have overshadowed its possible health beneficial effects. Currently, the success rate for treating neuropathic pain has been very low. This study investigated the antinociceptive effects of orally administered low dose lead acetate in sciatic nerve ligated Wistar rats. Thirty Wistar rats randomly divided into five groups were used for this study. Chronic constriction injury (CCI) was used to induce neuropathic pain in Wistar rats. Allodynic and hyperalgesic signs were investigated using von Frey filaments and hotplate, respectively. Morris water maze test was used to assess the memory functions of the rats. The study revealed that oral administration of low-dose lead acetate significantly (p < 0.05) increased pain thresholds of ligated rats. CCI enhanced memory function in Wistar rats which was significantly decreased following lead acetate administration. The findings suggest that lead acetate possesses antinociceptive effects in peripherally induced neuropathic pain model in Wistar rats.