Background: Current therapies for PD ameliorate symptoms in the early phases of disease but becom... more Background: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. Methods: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. Results: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.
Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycli... more Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal d... more We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP þ 3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a ''neuronal rescue'' strategy by administering riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and riluzole groups (10 mg=kg and 20 mg=kg), matched by triplets for motor severity. While riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, riluzole has limited ''neuronal rescue'' properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP þ 3-NP-induced SND in mice.
We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA appr... more We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CA... more Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.
Introduction: The atypical parkinsonian disorder known as striatonigral degeneration (SND) is a s... more Introduction: The atypical parkinsonian disorder known as striatonigral degeneration (SND) is a sporadic neurodegenerative disease characterized by a combined striatal and nigral degeneration. The aim of the study was to explore long term behavioral and histopathological consequences of MPTP+3-NP induced striato-nigral degeneration in C57BL/6 mice. Methods: The time course and severity of the motor disorder and cognitive dysfunctions, and their histopathological correlates were studied after 3-NP, MPTP or MPTP+3-NP intoxication compared to controls. Results: Although both 3-NP and MPTP+3-NP-treated mice developed motor symptoms, including hindlimb dystonia-clasping, truncal dystonia and impaired balance adjustements, severity of motor disorder was worse and lasted longer (5 weeks) in MPTP + 3-NP-treated mice. Both 3-NP and MPTP + 3-NP groups also displayed impaired motor performances on the pole test, the rotarod, the traversing a beam task and on open-field activity parameters compared to MPTP and saline mice. These sensorimotor deficits also lasted longer in MPTP+3-NP-intoxicated mice. By week7, MPTP+3-NP mice displayed altered cognitive performances compared to 3-NP and MPTP mice, notably procedural learning and spatial memory impairments, attentional deficits and increasing reactivity to novelty. Histopathology analysis demonstrated increased neuronal loss along with astrocytic activation (GFAP) in the striatum and SNc dopaminergic neurons of MPTP+3-NP-treated mice. Conclusion: Altogether, these results suggest that combined systemic MPTP+3-NP intoxication may constitute a useful phenotypic mouse model of SND, including cognitive deficits.
Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of d... more Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose = 450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose = 90 mg/kg in 9 days). Four groups of mice (n = 10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.
Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. ... more Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic`low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knockout mice (DAT ±/±) compared to wildtype (DAT +/+) mice. Systemic`low-dose' 3-NP induced a signi®cant impairment in a rotarod task only in DAT ±/± mice. Histopathology also demonstrated a signi®cant reduction of the striatal volume (±7%, P < 0.05), neuronal density (±12.5%, P < 0.001) and absolute number estimates of striatal neurons (±11.5%, P < 0.001) in DAT ±/± compared to DAT +/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These ®ndings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system.
Minocycline has been shown to exert anti-in¯ammatory effects underlying its putative neuroprotect... more Minocycline has been shown to exert anti-in¯ammatory effects underlying its putative neuroprotective properties in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and signi®cantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented signi®cantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mM cortical neurons) but not at higher doses (10 mM). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.
Initial studies conducted on the neuroprotective effects of minocycline, a second-generation tetr... more Initial studies conducted on the neuroprotective effects of minocycline, a second-generation tetracycline, in experimental models of neurodegeneration gave promising results. However, more recently, minocycline has clearly been shown to have variable and even contradictory (beneficial or detrimental) effects in different species and models of neurological disorders, and its ''neuroprotective'' mechanisms remain to be clarified. Although its anti-inflammatory properties are likely to contribute to its neuroprotective effects observed in several animal models, a body of recent evidence indicates that our community should proceed with caution in the clinical use of minocycline for central nervous system disorders.
Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.
Background: Current therapies for PD ameliorate symptoms in the early phases of disease but becom... more Background: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. Methods: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. Results: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.
Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycli... more Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01); however, 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal d... more We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP þ 3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a ''neuronal rescue'' strategy by administering riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and riluzole groups (10 mg=kg and 20 mg=kg), matched by triplets for motor severity. While riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, riluzole has limited ''neuronal rescue'' properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP þ 3-NP-induced SND in mice.
We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA appr... more We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of striatonigral degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CA... more Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.
Introduction: The atypical parkinsonian disorder known as striatonigral degeneration (SND) is a s... more Introduction: The atypical parkinsonian disorder known as striatonigral degeneration (SND) is a sporadic neurodegenerative disease characterized by a combined striatal and nigral degeneration. The aim of the study was to explore long term behavioral and histopathological consequences of MPTP+3-NP induced striato-nigral degeneration in C57BL/6 mice. Methods: The time course and severity of the motor disorder and cognitive dysfunctions, and their histopathological correlates were studied after 3-NP, MPTP or MPTP+3-NP intoxication compared to controls. Results: Although both 3-NP and MPTP+3-NP-treated mice developed motor symptoms, including hindlimb dystonia-clasping, truncal dystonia and impaired balance adjustements, severity of motor disorder was worse and lasted longer (5 weeks) in MPTP + 3-NP-treated mice. Both 3-NP and MPTP + 3-NP groups also displayed impaired motor performances on the pole test, the rotarod, the traversing a beam task and on open-field activity parameters compared to MPTP and saline mice. These sensorimotor deficits also lasted longer in MPTP+3-NP-intoxicated mice. By week7, MPTP+3-NP mice displayed altered cognitive performances compared to 3-NP and MPTP mice, notably procedural learning and spatial memory impairments, attentional deficits and increasing reactivity to novelty. Histopathology analysis demonstrated increased neuronal loss along with astrocytic activation (GFAP) in the striatum and SNc dopaminergic neurons of MPTP+3-NP-treated mice. Conclusion: Altogether, these results suggest that combined systemic MPTP+3-NP intoxication may constitute a useful phenotypic mouse model of SND, including cognitive deficits.
Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of d... more Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose = 450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose = 90 mg/kg in 9 days). Four groups of mice (n = 10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.
Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. ... more Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic`low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knockout mice (DAT ±/±) compared to wildtype (DAT +/+) mice. Systemic`low-dose' 3-NP induced a signi®cant impairment in a rotarod task only in DAT ±/± mice. Histopathology also demonstrated a signi®cant reduction of the striatal volume (±7%, P < 0.05), neuronal density (±12.5%, P < 0.001) and absolute number estimates of striatal neurons (±11.5%, P < 0.001) in DAT ±/± compared to DAT +/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These ®ndings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system.
Minocycline has been shown to exert anti-in¯ammatory effects underlying its putative neuroprotect... more Minocycline has been shown to exert anti-in¯ammatory effects underlying its putative neuroprotective properties in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and signi®cantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented signi®cantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mM cortical neurons) but not at higher doses (10 mM). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.
Initial studies conducted on the neuroprotective effects of minocycline, a second-generation tetr... more Initial studies conducted on the neuroprotective effects of minocycline, a second-generation tetracycline, in experimental models of neurodegeneration gave promising results. However, more recently, minocycline has clearly been shown to have variable and even contradictory (beneficial or detrimental) effects in different species and models of neurological disorders, and its ''neuroprotective'' mechanisms remain to be clarified. Although its anti-inflammatory properties are likely to contribute to its neuroprotective effects observed in several animal models, a body of recent evidence indicates that our community should proceed with caution in the clinical use of minocycline for central nervous system disorders.
Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.
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