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  1. Zinc: indications in brain disorders
    Prakash A, Bharti K, Majeed AB
    Fundam Clin Pharmacol, 2015 Apr;29(2):131-49.
    PMID: 25659970 DOI: 10.1111/fcp.12110
    Zinc is the authoritative metal which is present in our body, and reactive zinc metal is crucial for neuronal signaling and is largely distributed within presynaptic vesicles. Zinc also plays an important role in synaptic function. At cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Different importers and transporters are involved in zinc homeostasis. ZnT-3 is a main transporter involved in zinc homeostasis in the brain. It has been found that alterations in brain zinc status have been implicated in a wide range of neurological disorders including impaired brain development and many neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Furthermore, zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.
  2. Possible role of metal ionophore against zinc induced cognitive dysfunction in D-galactose senescent mice
    Bharti K, Majeed AB, Prakash A
    Biometals, 2016 Jun;29(3):399-409.
    PMID: 26923568 DOI: 10.1007/s10534-016-9922-8
    Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid β (Aβ) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-β. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.
  3. The role of multifunctional drug therapy against carbamate induced neuronal toxicity during acute and chronic phase in rats
    Chahal KS, Prakash A, Majeed AB
    Environ Toxicol Pharmacol, 2015 Jul;40(1):220-9.
    PMID: 26151868 DOI: 10.1016/j.etap.2015.06.002
    The current study has been designed to examine the effect of multifunctional drug therapy on carbofuran induced acute (2.187 mg/kg, s.c.) and sub-acute (0.2187 mg/kg, s.c.) neurotoxicity in male wistar rats. Drug treatment which includes nimodipine (Ca(2+) channel blocker), diazepam, ropinirole (dopamine agonist) and GSPE (antioxidant) was started 2h after carbofuran administration. Morris water maze was employed for aiming spatial memory. Narrow beam walk and rotarod were employed for testing motor functions. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite, reduced glutathione, catalase levels, and mitochondrial complexes were also estimated. Carbofuran treatment resulted in significant development of cognitive and motor functions manifested as impairment in learning and memory along with increased thiobarbituric acid reactive species, nitrite levels and decreased acetylcholinesterase activity, reduced glutathione, catalase levels, and mitochondrial complexes. The standard antidote therapy (atropine) was not able to provide neuroprotection but was able to provide symptomatic relief. The multifunctional drug therapy attenuated carbofuran induced cognitive and motor dysfunction, acetylcholinesterase activity and other biochemical parameters. The triple combination in sub-acute study may be avoided in future as two drug combinations provide adequate neuroprotection. Thus it can be concluded that standard antidotal therapy may not provide neuroprotection while the multifunctional drug therapy offers neuroprotection against carbofuran and may dramatically increase survival and life quality.
  4. Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets
    Prakash A, Kalra J, Mani V, Ramasamy K, Majeed AB
    Expert Rev Neurother, 2015 Jan;15(1):53-71.
    PMID: 25495260 DOI: 10.1586/14737175.2015.988709
    Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression.
  5. Fulltext Candida sake--a rare cause of fungal endocarditis
    Anuradha S, Agarwal SK, Prakash A, Singh NP, Kaur R
    Med J Malaysia, 2008 Mar;63(1):75-6.
    PMID: 18935744
  6. Brain biometals and Alzheimer's disease - boon or bane?
    Prakash A, Dhaliwal GK, Kumar P, Majeed AB
    Int J Neurosci, 2017 Feb;127(2):99-108.
    PMID: 27044501
    Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. A complicated array of molecular events has been implicated in the pathogenesis of AD. It is attributed to a variety of pathological conditions that share similar critical processes, such as oxidative stress, proteinaceous aggregations, mitochondrial dysfunctions and energy failure. There is increasing evidence suggesting that metal homeostasis is dysregulated in the pathology of AD. Biometals play an important role in the normal body functioning but AD may be mediated or triggered by disproportion of metal ions leading to changes in critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. The link is multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper (Cu) and other trace metals. Their levels in the brain are found to be elevated in AD. In other neurodegenerative disorders, Cu, zinc, aluminum and manganese are involved. This paper is a review of recent advances of the role of metals in the pathogenesis and pathophysiology of AD and related neurodegenerative diseases.
  7. Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats
    Kalra J, Kumar P, Majeed AB, Prakash A
    Pharmacol. Biochem. Behav., 2016 Jul-Aug;146-147:1-12.
    PMID: 27106205 DOI: 10.1016/j.pbb.2016.04.002
    Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.
  8. Cerebroprotective effects of RAS inhibitors: Beyond their cardio-renal actions
    Kalra J, Prakash A, Kumar P, Majeed AB
    J Renin Angiotensin Aldosterone Syst, 2015 Sep;16(3):459-68.
    PMID: 25944853 DOI: 10.1177/1470320315583582
    Work on the brain renin-angiotensin system has been explored by various researchers and has led to elucidation of its basic physiologies and behavior, including its role in reabsorption and uptake of body fluid, blood pressure maintenance with angiotensin II being its prominent effector. Currently, this system has been implicated for its newly established effects, which are far beyond its cardio-renal effects accounting for maintenance of cerebral blood flow and cerebroprotection, seizure, in the etiology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and bipolar disorder. In this review, we have discussed the distribution of angiotensin receptor subtypes in the central nervous system (CNS) together with enzymatic pathways leading to active angiotensin ligands and its interaction with angiotensin receptor 2 (AT2) and Mas receptors. Secondly, the use of angiotensin analogues (angiotensin converting enzyme inhibitors and AT1 and/or AT2 receptor blockers) in the treatment and management of the CNS disorders mentioned above has been discussed.
  9. Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction
    Prakash A, Kumar A, Ming LC, Mani V, Majeed AB
    J Mol Neurosci, 2015 Jul;56(3):739-50.
    PMID: 25854775 DOI: 10.1007/s12031-015-0508-7
    Alzheimer's disease (AD) is a neurodegenerative disease characterized by impaired memory function and oxidative damage. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through modulating nitric oxide synthase. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. The present study was designed to investigate the possible nitric oxide mechanism in the protective effect of pioglitazone against streptozotocin (STZ)-induced memory dysfunction. Wistar rats were intracerebroventricularly (ICV) injected with STZ. Then rats were treated with pioglitazone, NO modulators [L-arginine and nitro-L-arginine methyl ester (L-NAME)] for 21 days. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and mito-oxidative parameters, TNF-α, IL-6, and caspase-3 activity were measured. STZ-treated rats showed a memory deficit and significantly increased in mito-oxidative damage and inflammatory mediators and apoptosis in the hippocampus. Chronic treatment of pioglitazone significantly improved memory retention and attenuated mito-oxidative damage parameters, inflammatory markers, and apoptosis in STZ-treated rats. However, L-arginine pretreatment with lower dose of pioglitazone has not produced any protective effect as compared to per se. Furthermore, pretreatment of L-NAME significantly potentiated its protective effect, which indicates the involvement of nitric oxide for activation of PPAR-γ action. These results demonstrate that pioglitazone offers protection against STZ-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, and anti-apoptotic action mediating nitric oxide pathways and, therefore, could have a therapeutic potential in AD.
  10. Fulltext Comparative evaluation of salivary immunoglobulin a levels between pedodontic subjects
    Jha A, Singh R, Jha S, Singh S, Chawla R, Prakash A
    J Family Med Prim Care, 2020 Apr;9(4):2052-2055.
    PMID: 32670964 DOI: 10.4103/jfmpc.jfmpc_967_19
    Background and Aims: Host immune response is altered by a series of physiologic and pathologic factors like age, gender, inflammation, surgery, medication etc., The present study was conducted to evaluate differences in salivary IgA (S-IgA) levels among pedodontic subjects undergoing active orthodontic treatment with fixed and removable appliance. The levels of S- IgA were determined before 3 months and 6 months post active orthodontic treatment.

    Methods: A total of 40 healthy pedodontic subjects (aged 8-15 years) were recruited in the present study. They were equally divided into Group A (fixed orthodontic group) and Group B (removable orthodontic group) with 20 subjects each. 1.5 mL of saliva per subject was obtained before 3 and 6 months after treatment. Enzyme Linked Immunosorbent Assay (ELISA) technique was used for measurement of Salivary IgA levels.

    Results: Group A and B both showed significant rise in S-IgA levels 3 months and 6 months post active orthodontic treatment. Mean value of S-IgA 3 months post treatment in the saliva of children in group B and group A were (144.27 ± 5.32) and (164.0 ± 3.23) μg/ml respectively. While mean value of S-IgA after 6 months of treatment in group B and group A were (149.8 ± 6.02) and (166.4 ± 3.65) μg/ml respectively.

    Conclusion: Salivary Immunoglobulin A level values were significantly higher statistically in both group A and group B post active orthodontic treatment than before. The results however, showed that Group A (fixed orthodontic group) showed statistically significant higher levels of S-IgA than Group B (removable orthodontic group). Active orthodontic treatment triggered a stronger stimulus for oral secretory immunity, hence the increase in levels were detected. There is a significant positive correlation between S-IgA and active fixed as well as removable orthodontic treatment. Orthodontic treatment is hence a local immunogenic factor.

  11. Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats
    Singh H, Prakash A, Kalia AN, Majeed AB
    J Tradit Complement Med, 2016 Oct;6(4):370-376.
    PMID: 27774421
    Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties.
  12. Fulltext Message framing and COVID-19 vaccine acceptance among millennials in South India
    Prakash A, Jeyakumar Nathan R, Kini S, Victor V
    PLoS One, 2022;17(7):e0269487.
    PMID: 35802760 DOI: 10.1371/journal.pone.0269487
    Vaccine hesitancy and refusal remain a major concern for healthcare professionals and policymakers. Hence, it is necessary to ascertain the underlying factors that promote or hinder the uptake of vaccines. Authorities and policy makers are experimenting with vaccine promotion messages to communities using loss and gain-framed messages. However, the effectiveness of message framing in influencing the intention to be vaccinated is unclear. Based on the Theory of Planned Behaviour (TPB), this study analysed the impact of individual attitude towards COVID-19 vaccination, direct and indirect social norms, perceived behavioural control and perceived threat towards South Indian millennials' intention to get vaccinated. The study also assessed the effect of framing vaccine communication messages with gain and loss framing. Data was collected from 228 Millennials from South India during the COVID-19 pandemic from September to October 2021 and analysed using PLS path modelling and Necessary Condition Analysis (NCA). The findings reveal that attitudes towards vaccination, perceived threat and indirect social norms positively impact millennials' intention to take up vaccines in both message frames. Further, independent sample t-test between the framing groups indicate that negative (loss framed message) leads to higher vaccination intention compared to positive (gain framed message). A loss-framed message is thus recommended for message framing to promote vaccine uptake among millennials. These findings provide useful information in understanding the impact of message framing on behavioural intentions, especially in the context of vaccine uptake intentions of Millennials in South India.
  13. Possible role of GABA-B receptor modulation in MPTP induced Parkinson's disease in rats
    Tyagi RK, Bisht R, Pant J, Kumar P, Majeed AB, Prakash A
    Exp. Toxicol. Pathol., 2015 Feb;67(2):211-7.
    PMID: 25547370 DOI: 10.1016/j.etp.2014.12.001
    Accumulating evidence strongly suggests that gamma amino butyric acid (GABA) receptors play a crucial role in the pathogenesis of Parkinson's disease (PD). Therefore, the present study was designed to investigate the role of GABA-B receptor modulation in experimental models of MPTP-induced PD. MPTP was administered repeatedly on 1st, 7th and 14th day intranigrally for the induction of PD in Male Wistar rats. Baclofen (10 and 20mg/kg) and GABA-B antagonist CGP35348 (10mg/kg) were given after induction of PD for 14 days. Different behavioural tasks were performed during 1st, 14th, 21st, 28th days after MPTP injection and biochemical parameters were estimated on day 28th. Central administration of MPTP showed significant impairment of motor behaviour and marked increase of oxidative damage LPO and GSH in striatum and cortex. Pro-inflammatory cytokines like TNF-α and IL-β were significantly increased in striatum region of MPTP treated rats. However, post treatment with baclofen significantly improved the motor abnormalities and attenuated the oxidative damage and neuro-inflammation in MPTP treated rats. CGP35348, GABA-B receptor antagonist, reversed the protective effect of baclofen GABA-B receptor play role in the neuroprotection. The present study concluded that baclofen produce beneficial effect against MPTP induced PD like symptoms rats through GABAergic mechanism.
  14. Pharmacological evaluation of nasal delivery of selegiline hydrochloride-loaded thiolated chitosan nanoparticles for the treatment of depression
    Singh D, Rashid M, Hallan SS, Mehra NK, Prakash A, Mishra N
    Artif Cells Nanomed Biotechnol, 2016 May;44(3):865-77.
    PMID: 26042481 DOI: 10.3109/21691401.2014.998824
    The aim of the present study was to investigate the propensity of thiolated chitosan nanoparticles (TCNs) to enhance the nasal delivery of selegiline hydrochloride. TCNs were synthesized by the ionic gelation method. The particle size distribution (PDI), entrapment efficiency (EE), and zeta potential of modified chitosan (CS) nanoparticles were found to be 215 ± 34.71 nm, 70 ± 2.71%, and + 17.06 mV, respectively. The forced swim and the tail suspension tests were used to evaluate the anti-depressant activity, in which elevated immobility time was found to reduce on treatment. TCNs seem to be promising candidates for nose-to-brain delivery in the evaluation of antidepressant activity.
  15. Recent prospective of surface engineered Nanoparticles in the management of Neurodegenerative disorders
    Singh D, Kapahi H, Rashid M, Prakash A, Majeed AB, Mishra N
    Artif Cells Nanomed Biotechnol, 2016 May;44(3):780-91.
    PMID: 26107112 DOI: 10.3109/21691401.2015.1029622
    Clinically, the therapeutic outcomes in neurodegenerative disorders (NDs) by drug treatment are very limited, and the most insurmountable obstacle in the treatment of NDs is the blood-brain barrier (BBB), which provides the highest level of protection from xenobiotics. A great deal of attention still needs to be paid to overcome these barriers, and surface-engineered polymeric nanoparticles are emerging as innovative tools that are able to interact with the biological system at a molecular level for the desired response. The present review covers the potential importance of surface-structure-engineered nanoparticles to overcome the BBB for good bioavailability, and the evaluation of drug therapy in NDs.
  16. The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides
    Singh S, Prakash A, Kaur S, Ming LC, Mani V, Majeed AB
    Environ Toxicol, 2016 Aug;31(8):1017-26.
    PMID: 25864908 DOI: 10.1002/tox.22111
    Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.
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