Neural functions of the aging brain: Daily living, developmental and geriatric disabilities.

Neuronal, microglial, astrocytic and oligodendrocytic functions of the brain are significantly affected during normal aging, and more so if inflicted with neurological diseases. Aging is a consistent risk factor for many neurodegenerative diseases that are sporadic in nature, whereas developmental neurological disabilities stem from errors in brain development. The neuronal functions are affected in both developmental disabilities and geriatric diseases. This special issue, is based on the two-days meeting at Thiruvanathapuram, India on 'Neural Functions of Aging Brain', which had several original presentations, as well as full reviews by neurobiologists and clinicians from India. Out of these, thirteen peer reviewed contributions are published in the present Special Issue of this Journal. This 'Foreword' is also a brief overview on the current scenario of neurobiology research on developmental disabilities and ageing in India based on the manuscripts included in the special issue, vis-s-vis the global scenario. Apparently, there is a void in geriatric and developmental neuroscience research in India since huge data mining and translation, concerted efforts on clinical neuroscience research, and consistent efforts on pure basic research resulting in 'first in the field' novelty are largely missing. Overall, Indian neuroscience excels in making meaningful relevance of contemporary discoveries in neuroscience and contributing towards advances in their applications.

Reinforcing mitochondrial functions in aging brain: An insight into Parkinson's disease therapeutics.

Mitochondria, the powerhouse of the neural cells in the brain, are also the seat of certain essential gene signaling pathways that control neuronal functions. Deterioration of mitochondrial functions has been widely reported in normal aging as well as in a spectrum of age-associated neurological diseases, including Parkinson's disease (PD). Evidences accumulated in the recent past provide not only advanced information on the causes of mitochondrial bioenergetics defects and redox imbalance in PD brains, but also much insight into mitochondrial biogenesis, quality control of mitochondrial proteins, and genes, which regulate intra- and extra-mitochondrial signaling that control the general health of neural cells. The mitochondrial quality control machinery is affected in aging and especially in PD, thus affecting intraneuronal protein transport and degradation, which are primarily responsible for accumulation of misfolded proteins and mitochondrial damage in sporadic as well as familial PD. Essentially we considered in the first half of this review, mitochondria-based targets such as mitochondrial oxidative stress and mitochondrial quality control pathways in PD, relevance of mitochondrial DNA mutations, mitophagy, mitochondrial proteases, mitochondrial flux, and finally mitochondria-based therapies possible for PD. Therapeutic aspects are considered in the later half and mitochondria-targeted antioxidant therapy, mitophagy enhancers, mitochondrial biogenesis boasters, mitochondrial dynamics modulators, and gene-based therapeutic approaches are discussed. The present review is a critical assessment of this information to distinguish some exemplary mitochondrial therapeutic targets, and provides a utilitarian perception of some avenues for therapeutic designs on identified mitochondrial targets for PD, a very incapacitating disorder of the geriatric population, world over.

Plant-Derived Natural Products for Parkinson's Disease Therapy.

Plant-derived natural products have made their own niche in the treatment of neurological diseases since time immemorial. Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, has no cure and the treatment available currently is symptomatic. This chapter thoughtfully and objectively assesses the scientific basis that supports the increasing use of these plant-derived natural products for the treatment of this chronic and progressive disorder. Proper considerations are made on the chemical nature, sources, preclinical tests and their validity, and mechanisms of behavioural or biochemical recovery observed following treatment with various plants derived natural products relevant to PD therapy. The scientific basis underlying the neuroprotective effect of 6 Ayurvedic herbs/formulations, 12 Chinese medicinal herbs/formulations, 33 other plants, and 5 plant-derived molecules have been judiciously examined emphasizing behavioral, cellular, or biochemical aspects of neuroprotection observed in the cellular or animal models of the disease. The molecular mechanisms triggered by these natural products to promote cell survivability and to reduce the risk of cellular degeneration have also been brought to light in this study. The study helped to reveal certain limitations in the scenario: lack of preclinical studies in all cases barring two; heavy dependence on in vitro test systems; singular animal or cellular model to establish any therapeutic potential of drugs. This strongly warrants further studies so as to reproduce and confirm these reported effects. However, the current literature offers scientific credence to traditionally used plant-derived natural products for the treatment of PD.

Neuro-nutraceuticals: Further insights into their promise for brain health.

In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address key emergent issues such as bioavailability, neuronal health, inflammation and the holistic benefit of multi-targeted actions that impact upon how nutraceuticals ultimately leverage the brain to function better. In terms of the benefit of nutraceuticals it is clear that some naturally occurring molecules can be advantageous to both the young and aged brain, and that they have actions that ultimately can be directed to aid either in the improvement of cognition or in the management of debilitating neurodegenerative and neuropsychiatric conditions.

Quercetin improves the activity of the ubiquitin-proteasomal system in 150Q mutated huntingtin-expressing cells but exerts detrimental effects on neuronal survivability.

Quercetin, a strong free radical scavenger, is investigated for neuroprotective effects in a Neuro 2a cell line conditionally transfected with 16Q huntingtin (Htt) and 150Q Htt, which express the protein upon stimulation. Cells were protected from death by a 20-µM dose of quercetin on the second day of Htt induction, but 30-100-µM doses of the drug caused further toxicity in both 16Q and 150Q cells, as indicated by MTT assay and by significant reductions in the number of cells bearing neurites on the second day. A significant decrease in the number of cells containing aggregate was seen in induced 150Q cells treated with 20 µM but not for those treated with 40 or 50 µM quercetin up to 4 days of induction. Mutated Htt (mHtt)-induced reduction in proteasomal activity of the ubiquitin-proteasomal system (UPS) was significantly attenuated by 20 µM quercetin. However, neither mitochondrial membrane potential loss nor colocalization of 20S proteasome with mHtt aggregate was corrected by quercetin treatment. Our results imply that the neuroprotective effect of quercetin arises out of the upregulation of UPS activity, which causes a decrease in the number of mHtt aggregate-harboring cells. The increased neurotoxicity could result from the continued association of mHtt with 20S proteasome and the failure of quercetin to correct mitochondrial membrane potential loss. These results suggest that, although quercetin at a low dose protects against mHtt-mediated cell death, higher doses are toxic to the cells, clearly demarcating a narrow therapeutic window for this dietary flavonoid.

Antagonistic pleiotropic effects of nitric oxide in the pathophysiology of Parkinson's disease.

Sporadic Parkinson's disease (PD) is a geriatric disorder with unknown etiology, specifically affecting the nigrostriatal dopaminergic (DA-ergic) pathway of the brain. Amongst several contributing factors, nitric oxide (NO•) is considered to inflict injury to DA-ergic neurons, and to influence PD progression. Supportive evidence for this comes from animal models of PD, where inhibitors of NO• synthase (NOS) are found to protect against DA-ergic neuronal death, and NOS-deficient mice are found to be resistant to PD-producing neurotoxins. Presence of nitrated proteins and upregulated levels of NOS in human postmortem PD brain samples have rendered further support to this contention. While NO• from neuronal NOS contributes to neurodegeneration in PD, NO• produced by inducible NOS from proliferating microglia as inflammatory responses to neuronal insults are suggested to mediate the disease progression. Another view that NO• in small doses serves as a neuroprotective agent in the brain is also discussed, in light of experimental evidence available in vitro and in vivo. This view is based on the argument that NO• could form harmless nitrites and nitrates on reaction with endogenously produced reactive oxygen species (ROS) within the cells. This review essentially discusses the possibilities of considering NO• as a secondary response of DA-ergic cell death, while oxidative stress is the primary cause. Once neurons undergo death processes following uncontrolled oxidative insult, the resulting gliosis-mediated NO• accelerates the events as a secondary mediator. Since the time of initiation of DA-ergic cell death cannot be predicted, NO• could be an ideal molecular target to halt the disease progression.

Profilin-2 increased expression and its altered interaction with ß-actin in the striatum of 3-nitropropionic acid-induced Huntington's disease in rats.

Subacute systemic treatment with 3-nitropropionic acid (3-NP) causes specific lesions in the cortex and the striatum, and Huntington's disease behavioral phenotypes in rats. We investigated differentially expressed genes in the striatum, and examined status of a highly expressed huntingtin interacting protein, profilin 2 (Pfn2) in relation to 3-NP-induced striatal neurodegeneration, employing both in vivo animal model and in vitro primary striatal neuronal cultures. Golgi staining of 3-NP-treated rat brain revealed significantly altered dendritic spine morphology and decreased spine density in the cortex and the striatum, as compared to the control. We employed suppression subtractive hybridization (SSH) method to screen differentially expressed genes during striatal neurodegeneration in these animals. Forward and reverse SSH provided a library of 188 clones, which were used for reverse northern dot blot analysis to identify greatly altered striatal-specific genes. Sequence analysis of the clones identified 23 genes, expressions of which were ⩾1.5-fold changed (16 up-regulated) in the striatum of 3-NP-treated rats. Immunoprecipitation assay showed decreased binding of Pfn2 with ß-actin, the level of which remained unaffected in the striata and cortices of 3-NP-treated rats. Primary cultures of striatal glutamic acid decarboxylase-65/67 immunopositive GABAergic neurons revealed loss of co-existence of Pfn2 and ß-actin in fluorescence imaging studies following 3-NP treatment for 24h. Since Pfn2 is known to regulate dendritic spine dynamics by interacting with ß-actin, the reduction in its binding affinity to Pfn2 following 3-NP neurotoxic insult, and the accompanying aberrations of the dendritic spine structure and loss of spine density in striatal neurons suggest that Pfn2 may be involved in neurodegeneration in 3-NP-treated rat model of HD.

Potential contribution of monoamine oxidase a gene variants in ADHD and behavioral co-morbidities: scenario in eastern Indian probands.

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed behavioral disorder in children with a high frequency of co-morbid conditions like conduct disorder (CD) and oppositional defiant disorder (ODD). These traits are controlled by neurotransmitters like dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of amines, has been reported to be associated with aggression, impulsivity, depression, and mood changes. We hypothesized that MAOA can have a potential role in ADHD associated CD/ODD and analyzed 24 markers in a group of Indo-Caucasoid subjects. ADHD probands and controls (N = 150 each) matched for ethnicity and gender were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Appropriate scales were used for measuring CD and ODD traits. Markers were genotyped by PCR-based methods and data obtained analyzed using the Cocaphase program under UNPHASED. Only eight markers were found to be polymorphic. rs6323 "G" allele showed higher frequencies in ADHD (P = 0.0023), ADHD + CD (P = 0.03) and ADHD + ODD (P = 0.01) as compared to controls. Haplotype analysis revealed statistically significant difference for three haplotypes in ADHD cases (P < 0.02). Statistically significant differences were also noticed for haplotypes in ADHD + CD and ADHD + ODD cases (P < 0.01). LD analysis showed significant variation in different groups. Multidimensionality reduction analysis showed independent as well as interactive effects of markers. Genotypes showed correlation with behavioral problems in ADHD and ADHD + CD. We interpret that MAOA gene variants may contribute to the etiology of ADHD as well as associated co-morbid CD and ODD in this ethnic group.

Melatonin protects against behavioural dysfunctions and dendritic spine damage in 3-nitropropionic acid-induced rat model of Huntington's disease.

Huntington's disease (HD), an autosomal dominant neurodegenerative movement disorder in which striatal and cortical neurons are mostly affected, has no effective cure existing. A fungal neurotoxin and a potent inhibitor of mitochondrial electron transport chain complex II inhibitor, 3-nitropropionic acid (3-NP) is known to cause HD pathology, including lesions in the striatum and the cortex, and several behavioural syndromes in experimental animals. In the present study we examined the effect of melatonin on motor activities, neuronal morphology as revealed by Nissl and rapid Golgi staining, as well as GABA, glutamate and biogenic amine neurotransmitter levels in 3-NP-induced HD in rats. We found that melatonin (10, 20mg/kg, i.p.) administered 1h prior to 3-NP dose (20mg/kg; daily for 4 days) restored motor coordination ability as shown in gait, beam balancing, swim ability and performance on rotarod. However it failed to reduce 3-NP-induced striatal lesion core area, neuronal damage and the elevated levels of striatal dopamine. Melatonin administration partially restored 3-NP-induced loss of dendritic spines in the striatum and the cortex, and the reduction in cerebellar granule cell, but not hippocampal CA1 neuronal arborization. These findings collectively suggest that melatonin offers beneficial effects in correction of learning related fine motor adjustments, but not in behaviours unrelated to learning, by the restoration of striatal and cortical spines, and cerebellar granule cell arborization.

A mitochondrial basis for Huntington's disease: therapeutic prospects.

Huntington's disease (HD) is an autosomal dominant disease, with overt movement dysfunctions. Despite focused research on the basis of neurodegeneration in HD for last few decades, the mechanism for the site-specific lesion of neurons in the brain is not clear. All the explanations that partially clarify the phenomenon of neurodegeneration leads to one organelle, mitochondrion, which is severely affected in HD at the level of electron transport chain, Ca(2+) buffering efficiency and morphology. But, with the existing knowledge, it is not clear whether the cell death processes in HD initiate from mitochondria, though the Huntingtin (Htt) aggregates show close proximity to this organelle, or do some extracellular stimuli like TNFα or FasL trigger the process. Mainly because of the disparity in the different available experimental models, the results are quite confusing or at least inconsistent to a great extent. The fact remains that the mutant Htt protein was seen to be associated with mitochondria directly, and as the striatum is highly enriched with dopamine and glutamate, it may make the striatal mitochondria more vulnerable because of the presence of dopa-quinones, and due to an imbalance in Ca(2+). The current therapeutic strategies are based on symptomatic relief, and, therefore, mainly target neurotransmitter(s) and their receptors to modulate behavioral outputs, but none of them targets mitochondria or try to address the basic molecular events that cause neurons to die in discrete regions of the brain, which could probably be resulting from grave mitochondrial dysfunctions. Therefore, targeting mitochondria for their protection, while addressing symptomatic recovery, holds a great potential to tone down the progression of the disease, and to provide better relief to the patients and caretakers.

Parkinson's disease cybrids, differentiated or undifferentiated, maintain morphological and biochemical phenotypes different from those of control cybrids.

SH-SY5Y, control, and Parkinson's disease (PD) cybrids prepared from an Indian population were differentiated using retinoic acid (RA) for understanding their dopaminergic characteristics and neuritogenesis. Undifferentiated control and PD cybrids exhibited higher levels of TH mRNA, but lower c-RET expression, short neurites, low neuritic density, and low proportion of cells with neurites compared with the undifferentiated parent cell line, SH-SY5Y. The expression levels of DAT and Ptx3 were similar to SH-SY5Y. PD cybrids showed poor viability and lower differentiating potency than SH-SY5Y or control cybrids. RA treatment for 6 days elevated c-RET expression and corrected the neuritic morphology of the control, but not of PD cybrids. Cell viability was found to be reduced in differentiated control and PD cybrids. TH expression level was significantly elevated in SH-SY5Y following RA treatment, but not in both the cybrids. In differentiated control and PD cybrids, the TH immunofluorescence intensity was significantly lower compared with SH-SY5Y cells. MitoTracker Green fluorescence intensity of the mitochondria was higher in differentiated PD cybrids. Dopamine released into the medium was unaffected in the differentiated SH-SY5Y or in the control cybrids but was significantly elevated in PD cybrids. These results suggest that PD cybrids, differentiated or undifferentiated, maintained morphological and biochemical phenotypes significantly different from those of the control cybrids, or the differentiated SH-SY5Y cells, and therefore could be an ideal cellular model of the disease for pharmacological screening of drugs and for investigation of the pathophysiology of PD.

Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson's disease in rats.

We tested quercetin, a dietary bioflavonoid with potent free radical scavenging action and antioxidant activity, for its neuroprotective effects in rotenone-induced hemi-parkinsonian rats. Rats were infused unilaterally with rotenone into the substantia nigra, and quercetin (25-75mg/kg, i.p.) was administered at 12-h intervals for 4days, and analyzed on the 5th day. Amphetamine- or apomorphine-induced unilateral rotations were significantly reduced in quercetin-treated rats, when analyzed on 14th or 16th day post-surgery, respectively. Quercetin possessed potent hydroxyl radical scavenging action in a cells-free, Fenton-like reaction in test tubes, and in isolated mitochondria when measured by salicylate hydroxylation method. We observed dose-dependent attenuation of the rotenone-induced loss in striatal dopamine, and nigral oxidized and reduced glutathione, as well as the increases in endogenous antioxidant enzymes (catalase and superoxide dismutase) activities supporting the notion that quercetin-effect is mediated via its powerful hydroxyl radicals-scavenging and antioxidant actions. Quercetin's dose-dependent ability to up-regulate mitochondrial complex-I activity, as evidenced by NADH-oxidation, and as seen in blue native-polyacrylamide gel electrophoresis (PAGE) staining in both the contra- and ipsi-lateral nigra suggests the containment of reactive oxygen production at the mitochondrial level. Rotenone-induced induction of NADH-diaphorase activity in the nigral neurons, and its attenuation by quercetin pointed to the possible involvement of nitric oxide too. Reversal of neuronal death induced by rotenone as observed by increased tyrosine hydroxylase-positive cells and decreased TdT-mediated dUTP nick end-labeling (TUNEL) staining in the substantia nigra confirmed the potential of quercetin to revamp dopaminergic cells following oxidative stress mediated programmed cell death and neuronal demise. The present study strongly implicates quercetin's potential ability to repair mitochondrial electron transport defects and to up-regulate its function as the basis of neuroprotection observed in a mitochondrial neurotoxin-induced Parkinsonism.

Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats.

Rotenone is known to cause progressive dopaminergic neuronal loss in rodents, but it remains unclear how this mitochondrial complex-I inhibitor mediates neurodegeneration specific to substantia nigra pars compacta (SNpc). One of the proposed mechanisms is increased free radical generation owing to mitochondrial electron transport chain dysfunction following complex-I inhibition. The present study examined the role of nitric oxide (NO) and hydroxyl radicals (OH) in mediating rotenone-induced dopaminergic neurotoxicity. Indications of NO involvement are evidenced by inducible nitric oxide synthase (NOS) over-expression, and increased NADPH-diaphorase staining in SNpc neurons 96h following rotenone administration. Treatment of these animals with specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) and non-specific NOS inhibitor, N-ω-nitro-l-argenine methyl ester (l-NAME) caused reversal of rotenone-induced striatal dopamine depletion, and attenuation of the neurotoxin-induced decrease in the number of tyrosine hydroxylase immunoreactive neurons in SNpc, as well as in apomorphine and amphetamine-induced unilateral rotations. Interestingly, the study also demonstrated the contribution of OH in mediating rotenone nigral toxicity since there appeared a significant generation of the reactive oxygen species in vivo 24h following rotenone administration, a copious loss of reduced and oxidized glutathione, and increased superoxide dismutase and catalase activities in the cytosolic fractions of the ipsilateral SNpc area on the 5th day. An OH scavenging capacity of 7-NI and l-NAME in a Fenton-like reaction, as well as complete reversal of the rotenone-induced increases in the antioxidant enzyme activities, and the loss in reduced and oxidized glutathione contents in the SNpc supported OH involvement in rotenone-induced dopaminergic neurotoxicity. While these results strongly suggest the contribution of both OH and NO, resulting in acute oxidative stress culminating in dopaminergic neurodegeneration caused by rotenone, the course of events indicated generation of OH as the primary event in the neurotoxic processes.

Antiparkinsonian effects of aqueous methanolic extract of Hyoscyamus niger seeds result from its monoamine oxidase inhibitory and hydroxyl radical scavenging potency.

Hyoscyamus species is one of the four plants used in Ayurveda for the treatment of Parkinson's disease (PD). Since Hyoscyamus niger was found to contain negligible levels of L-DOPA, we evaluated neuroprotective potential, if any, of characterized petroleum ether and aqueous methanol extracts of its seeds in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. Air dried authenticated H. niger seeds were sequentially extracted using petroleum ether and aqueous methanol and were characterized employing HPLC-electrochemistry and LCMS. Parkinsonian mice were treated daily twice with the extracts (125-500 mg/kg, p.o.) for two days and motor functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing 0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia, catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. Since the extract caused significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+)-induced hydroxyl radical (·OH) generation in isolated mitochondria, it is possible that the methanolic extract of Hyoscyamus niger seeds protects against parkinsonism in mice by means of its ability to inhibit increased ·OH generated in the mitochondria.

2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice.

Behavioral and neurochemical effects of chronic administration of high doses of 2-phenylethylamine (PEA; 25-75 mg/kg, i.p. for up to 7 days) have been investigated in Balb/c mice. Depression and anxiety, as demonstrated respectively by increased floating time in forced swim test, and reduction in number of entries and the time spent in the open arms in an elevated plus maze were observed in these animals. General motor disabilities in terms of akinesia, catalepsy and decreased swimming ability were also observed in these animals. Acute and sub-acute administration of PEA caused significant, dose-dependent depletion of striatal dopamine, and its metabolites levels. PEA caused dose-dependent generation of hydroxyl radicals in vitro in Fenton's reaction in test tubes, in isolated mitochondrial fraction, and in vivo in the striatum of mice. A significant inhibition of NADH-ubiquinone oxidoreductase (complex-I; EC: 1.6.5.3) activity suggests the inhibition in oxidative phosphorylation in the mitochondria resulting in hydroxyl radical generation. Nissl staining and TH immnunohistochemistry in brain sections failed to show any morphological aberrations in dopaminergic neurons or nerve terminals. Long-term over-consumption of PEA containing food items could be a neurological risk factor having significant pathological relevance to disease conditions such as depression or motor dysfunction. However, per-oral administration of higher doses of PEA (75-125 mg/kg; 7 days) failed to cause such overt neurochemical effects in rats, which suggested safe consumption of food items rich in this trace amine by normal population.

Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues.

We have studied sporadic Parkinson's disease (sPD) from expression of patient mitochondrial DNA (mtDNA) in neural cells devoid of their own mtDNA, the "cybrid" model. In spite of reproducing several properties of sPD brain, it remains unclear whether sPD cybrid cells reflect more complex sPD brain bioenergetic pathophysiology. We characterized and correlated respiration of intact sPD cybrid cells with electron transport chain (ETC) protein assembly, complex I ETC gene expression and ETC protein levels in sPD brain. We also assayed expression for multiple ETC genes coded by mtDNA and nuclear DNA (nDNA) in sPD cybrid cells and brain. sPD cybrid cells have reduced levels of mtDNA genes, variable compensatory normalization of mitochondrial gene expression and show robust correlations with mitochondrial ETC gene expression in sPD brains. Relationships among ETC protein levels predict impaired complex I-mediated respiration in sPD brain. That sPD cybrid cells and sPD brain samples show very correlated regulation of nDNA and mtDNA ETC transcriptomes suggests similar bioenergetic physiologies. We propose that further insights into sPD pathogenesis will follow elucidation of mechanisms leading to reduced mtDNA gene levels in sPD cybrids. This will require characterization of the abnormalities and dynamics of mtDNA changes propagated through sPD cybrids over time.

Taurine fails to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion in mice.

Taurine, a known antioxidant and neuroprotector has been investigated for its free radical scavenging action in vitro in isolated mitochondria, and tested whether it protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in mice. Taurine (0.1-10 mM) did not affect 1-methyl-4-phenyl pyridinium-induced hydroxyl radical production in isolated mitochondria. Systemic administration of taurine (250 mg/kg, i.p.) caused a small, but significant loss of dopamine levels in the striatum of mice. Taurine failed to reverse MPTP-induced striatal dopamine depletion, but caused significant increase in dopamine turnover in these animals. In the light of the present study it may be suggested that consumption of taurine may neither help in scavenging of neurotoxic hydroxyl radicals in the brain mitochondria, nor would it help in blocking the process of neurodegeneration.

Acetaminophen and aspirin inhibit superoxide anion generation and lipid peroxidation, and protect against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats.

We assessed the antioxidant activity of non-narcotic analgesics, acetaminophen and aspirin in rat brain homogenates and neuroprotective effects in vivo in rats intranigrally treated with 1-methyl-4-phenyl pyridinium (MPP+). Both drugs inhibited cyanide-induced superoxide anion generation, as well as lipid peroxidation in rat brain homogenates, the combination of the agents resulting in a potentiation of this effect. Acetaminophen or aspirin when administered alone or in combination, did not alter dopamine (DA) levels in the forebrain or in the striatum. Intranigral infusion of MPP+ in rats caused severe depletion of striatal DA levels in the ipsilateral striatum in rats by the third day. Systemic post-treatment of acetaminophen afforded partial protection, whereas similar treatment of aspirin resulted in complete blockade of MPP+-induced striatal DA depletion. While these findings suggest usefulness of non-narcotic analgesics in neuroprotective therapy in neurodegenerative diseases, aspirin appears to be a potential candidate in prophylactic as well as in adjuvant therapy in Parkinson's disease.

Hypothyroidism in the developing rat brain is associated with marked oxidative stress and aberrant intraneuronal accumulation of neurofilaments.

The effects of hypothyroidism on parameters of oxidative stress and on intraneuronal distribution of neurofilaments have been investigated in the developing rat brain. Progressive hypothyroidism during the first 4 weeks of postnatal development led to an increase in superoxide dismutase and catalase activity, decline in the level of glutathione and mitochondrial cytochrome c oxidase activity and increase in the level of .OH radical along with enhanced protein carbonylation and lipid peroxidation. Immunocytochemical staining of cryostat sections of normal and hypothyroid cerebella from 25 day postnatal rats with anti neurofilament (NF) light chain (L) antibody showed aberrant accumulation of neurofilaments in the perikaryon of the hypothyroid Purkinje neurons in contrast to relatively uniform distribution in the controls. The morphological and biochemical alterations in the neurons of the developing hypothyroid brain are comparable to those seen in several neurodegenerative diseases.

Effects of p-chlorophenylalanine on striatal acetylcholinesterase activity and on biogenic amine levels in nuclei raphe and caudate-putamen during physostigmine-induced tremor in rats.

The biochemical mechanism underlying tremor is unknown. We investigated the effects of p-chlorophenylalanine (pCPA), a serotonin (5-HT) depletor, on the neurochemical processes in nuclei raphe dorsalis (NRD) and caudatus putamen (NCP) paralleling physostigmine-induced tremor in rats. Peak of physostigmine tremor correlated with increase in 5-HT in NRD and NCP, and a decrease in striatal dopamine (DA), as assayed employing high pressure liquid chromotography-electrochemistry. Administration of pCPA caused significant decrease in DA, norepinephrine (NE) and 5-HT levels in both the nuclei, without affecting striatal NE content and acetylcholinesterase activity. pCPA pretreatment significantly inhibited physostigmine-induced tremor and blocked corresponding increase in the levels of 5-HT in NRD and NCP. These results indicate involvement of central 5-HT, but not DA or NE, in the genesis of physostigmine tremor.