|
CNS
& Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 7, Number 3, June 2008
Contents
Proteases and Phospholipases in CNS Disorders
Guest Editor: Swapan K. Ray
Editorial Pp. 225-226
Therapeutic Strategy of Erythropoietin in Neurological
Disorders Pp. 227-234
Xiang-Bao Liu, Jiang-An Wang, Shan Ping
Yu, Christine L. Keogh and Ling Wei
[Abstract]
Targeting Extracellular Matrix Proteolysis for
Hemorrhagic Complications of tPA Stroke Therapy Pp.
235-242
Xiaoying Wang, Anna Rosell and
Eng H. Lo
[Abstract]
Tissue Plasminogen Activator (tPA) and Matrix
Metalloproteinases in the Pathogenesis of Stroke: Therapeutic
Strategies Pp. 243-253
Rao Muralikrishna Adibhatla and James
F. Hatcher
[Abstract]
Role of Secretory Phospholipase A2
in CNS Inflammation: Implications in Traumatic Spinal Cord
Injury Pp. 254-269
W. Lee Titsworth1, Nai-Kui Liu and
Xiao-Ming Xu
[Abstract]
New Insights into the Roles of Endolysosomal Cathepsins
in the Pathogenesis of Alzheimer’s Disease: Cathepsin
Inhibitors as Potential Therapeutics Pp.
270-277
Azizul Haque, Naren L. Banik and Swapan
K. Ray
[Abstract]
Beta-Secretase: Structure, Function, and Evolution
Pp. 278-294
Chitra Venugopal, Christina M. Demos, K.S.
Jagannatha Rao, Miguel A. Pappolla and Kumar Sambamurti
[Abstract]
Neuroprotection in Glaucoma Using Calpain-1
Inhibitors: Regional Differences in Calpain-1 Activity in
the Trabecular Meshwork, Optic Nerve and Implications for
Therapeutics Pp. 295-304
Bharathi Govindarajan, James Laird, Ronald Sherman,
Robert G. Salomon and Sanjoy K. Bhattacharya
[Abstract]
Calpain as a Potential Therapeutic Target in Parkinson’s
Disease Pp. 305-312
Supriti Samantaray, Swapan K. Ray and
Naren L. Banik
[Abstract]
Activation of Calpain and Caspase Pathways in
Demyelination and Neurodegeneration in Animal Model of Multiple
Sclerosis Pp. 313-320
Arabinda Das, M. Kelly Guyton, Jonathan
T. Butler, Swapan K. Ray and Naren L. Banik
[Abstract]
Abstracts
[Back to top]
Editorial
Proteases play important roles in the pathogenesis of injuries
and diseases of the central nervous system (CNS). Different
classes of proteases such as calpains, caspases, and cathepsins
may work independently or co-operatively to carry out the
proteolysis of key proteins in the CNS cells leading to cell
death and neurological problems [1-5]. Increased proteolytic
activities contribute to neurodegeneration in CNS injuries
such as ischemic brain injury (IBI), traumatic brain injury
(TBI), spinal cord injury (SCI) and also in CNS diseases such
as Alzheimer’s disease (AD), glaucoma, Pakinson’s
disease (PD), and multiple sclerosis (MS). Moreover, activation
of phospholipases can contribute to disruption of the blood-brain-barrier
(BBB) causing inflammation in the CNS disorders [6]. Contemporary
investigations in different laboratories have confirmed the
unequivocal roles of proteases and phospholipases in the pathogenesis
of these and other CNS disorders and suggested therapeutic
strategies for prevention of expression and activity of proteases
and phospholipases [7, 8]. I have the pleasure and privilege
to put forward to the readers this volume of the CNS &
Neurological Disorders – Drug Targets that contains
nine review articles from prominent research groups delineating
the roles of proteases and phospholipases in the pathogenesis
of IBI, TBI, SCI, AD, PD, and MS and also indicating the prospective
therapeutic strategies.
Liu et al. have described the enormous potential
of erythropoietin (EPO), a glycoprotein hormone and cytokine,
for the treatment of IBI, TBI, and PD. The mechanism of EPO
mediated amelioration of neurological disorders includes prevention
of neurodegeneration and promotion of angiogenesis and neurogenesis.
The therapeutic action of EPO is mediated through the EPO
receptor, which is expressed in the CNS cells. Therapeutic
efficacy of EPO includes decreases in ischemic infarct and
hemorrhage volume, and neuronal apoptosis, and increases in
survival rates in animal models. It is encouraging that some
clinical trials with EPO in neurological diseases have shown
desirable outcomes. Administration of EPO has proven to be
safe in animals and adult human patients, although safety
features of EPO in neonates and infants still need to be evaluated.
So far, available data suggest that EPO is poised to be a
promising therapeutic agent for the treatment of neurological
disorders.
Wang et al. have explained importance of targeting
extracellular matrix proteolysis for prevention of hemorrhagic
complications due to ischemic stroke therapy with the serine
protease tissue plasminogen activator (tPA), the only stoke
treatment approved by the US Food and Drug Administration
(FDA). Although the thrombolytic activity of tPA helps achieving
vascular reperfusion and clinical benefit, in reality tPA
is administered in only about 2-5% of stroke patients in the
US because of high risks of symptomatic intracranial hemorrhage
and low therapeutic time window to minimize hemorrhagic complications.
Currently, combination strategies are being explored to increase
thrombolytic efficacy of tPA for beneficial reperfusion with
simultaneous decrease in neurotoxicity and hemorrhagic complications.
Because dysregulated extracellular proteases initiate the
breakdown of neurovascular matrix to disrupt the BBB causing
edema and/or hemorrhage, targeting the extracellular matrix
proteolysis within the neurovascular unit may provide a new
strategy for improving the safety and efficacy of the thrombolytic
reperfusion therapy of stroke.
Adibhatla and Hatcher have cautioned that combination of the
thrombolytic activity of the serine protease tPA and the inhibition
of the matrix metalloproteases (MMPs) may not be a viable
therapeutic strategy for treatment of ischemic stroke. Use
of tPA as a thrombolytic therapy for stroke is also associated
with high risks of hemorrhage and inflammation due to the
factual possibility of disruption of the BBB with activation
of MMPs. Inhibition of MMPs may result in either beneficial
or detrimental effects depending on timing of treatment of
IBI. Although MMPs cause disruption of the BBB and neuronal
damage during early injury phase of stroke, MMPs also contribute
to vascular remodeling, angiogenesis, neurogenesis, and axonal
regeneration during the later repair phase of stroke. Any
treatment regimen targeted to MMPs must consider the conflicting
effects of MMPs during the early and later phases of IBI.
Titsworth et al. have presented the role of secretory
phospholipase A2 (sPLA2)
in inflammation in CNS disorders, especially in SCI. sPLA2
is a lipolytic enzyme and thus hydrolyzes the glycerophospholipids
to produce free fatty acids and lysophospholipids, which are
precursors of bioactive eicosanoids and platelet-activating
factor (PAF). In the mammalian CNS, there are more than ten
sPLA2 isozymes that play
diverse cellular responses, including host defense, phospholipid
digestion, and metabolism in physiological conditions but
under pathological situations, increased sPLA2
activity and excessive production of free fatty acids and
their metabolites lead to inflammation, loss of membrane integrity,
oxidative stress, and thereby tissue injury. Emerging results
suggest that sPLA2 plays
an important role in the secondary injury process in IBI,
TBI, and SCI. Because sPLA2
activity is induced by multiple mediators such as inflammatory
cytokines, free radicals, and excitatory amino acid during
progression of secondary injury process, and its activation
and metabolites are likely to aggravate the secondary injury.
Obviously, prevention of sPLA2
activity may provide novel and efficient therapeutic strategy
for controlling multiple pathways associated with the CNS
secondary injury.
Haque et al. have presented new insights into the
roles of endolysosomal proteases such as cysteinyl and aspartyl
cathepsins in the pathogenesis of AD and other neurodegenerative
diseases. Cysteinyl cathepsin B and aspartyl cathepsin D levels
are known to be upregulated in many neurological disorders
including AD, which is a leading cause of dementia in aged
individuals. Senile plaques, which lead to neuronal loss in
AD patients, contain amyloid-beta (Aβ
that is produced by proteolytic cleavage of the APP by the
proteases. This article accumulated the current understandings
of the cysteinyl and aspartyl cathepsins in cellular and molecular
events that lead to formation of senile plagues in AD. This
article also talked about cathepsin inhibitors as potential
treatment strategies to slow down or even prevent the formation
of senile plagues in this devastating neurological disorder.
Venugopal et al. have clarified the structure, function,
and evolution of beta-secretase (BACE-1) that initiates the
cleavage of Aβ
protein precursor (APP) leading to Aβ
aggregation, which is the pathological hallmark in AD. Because
BACE-1 mediated cleavage of APP is the limiting step for the
production of Aβ,
BACE-1 is a popular drug target to lower generation of Aβ.
Although BACE-2 was identified to be a homolog of BACE-1,
studies using knockout mice confirmed that BACE-1 was necessary
and sufficient for the generation of Aβ
in neurons. Development of drugs to target BACE-1, however,
has been sluggish due to lack of complete understanding of
the function and regulation of BACE-1 and also due to difficulties
in designing drugs to make permeable though the BBB to specifically
block the large catalytic pocket of BACE-1. Thus, this review
article accumulated the latest knowledge about the biological
properties of BACE-1 and attempted to use phylogenetic perspectives
to understand the function of BACE-1 so as to address the
future challenges in discovering drugs to selectively target
novel mechanisms of BACE-1 regulation for preventing formation
of Aβ
aggregation in AD patients.
Govindarajan et al. have illustrated the role calpain-1
in the pathogenesis leading to neurodegeneration in glaucoma
and also described the use of calpain-1 inhibitors for neuroprotection
in glaucoma. Glaucoma is a group of eye diseases that can
cause irreversible blindness in over 70 million people worldwide.
Accumulated evidences account for vast differences in processing
of calpain-1 in the trabecular meshwork (TM) and the optic
nerve. Systemic delivery of calpain-1 inhibitors could provide
neuroprotection and prevent progressive optic nerve damage
in glaucoma. Although calpain-1 is accumulated in the glaucomatous
TM tissues in vivo, calpain-1 activity is substantially
lower in the glaucomatous TM due to its partial degradation
and modification by lipid oxidation products such as iso[4]levuglandin
E2 (iso[4]LGE2).
Treatment of calpain-1 in vitro with iso[4]LGE2
causes covalent modification and inactivation of calpain-1,
making it resistant to protease digestion. Also, iso[4]LGE2-modified
calpain-1 undergoes ubiquitination in the TM and impairs the
cellular proteasome activity. In contrast, calpain-1 activity
was higher in glaucomatous optic nerve than control optic
nerve. Obviously, neuroprotection in glaucoma using calpain-1
inhibitors will require consideration of such anatomic differences
in calpain-1 activity and biosynthesis.
Samantaray et al. have proposed that calpain is involved
in degeneration of dopaminergic neurons and also motoneurons
in PD animals and PD patients and, therefore, calpain is a
potential therapeutic target in PD. Although degeneration
of dopaminergic neurons and inflammatory responses in the
mid-brain substantia nigra (SN) are well characterized, dopaminergic
replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA),
which is the precursor for dopamine synthesis, does neither
wholly rescue these neurons in SN nor effusively improve motor
function. Because persistent use of L-DOPA inflates the clinical
symptoms in PD patients, there is a possibility that other
areas of the CNS are also affected in this movement disorder.
This unique concept is presented in this review article with
evidences in support of involvement of calpain in degeneration
of spinal cord in two models of experimental parkinsonism,
one induced by the neurotoxin 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine
(MPTP) and another induced by the environmental toxin rotenone.
Calpain played a prominent role in disrupting the structural
and functional integrity of the spinal cord in these experimental
models of parkinsonism. Similar pathogenic role of calpain
was also observed in SN of PD patients as well as in experimental
PD animals. Thus, calpain appears to cause neurodegeneration
in both brain and spinal cord during pathogenesis of PD and
so calpain inhibition should be explored as a therapeutic
strategy in PD.
Das et al. have explicated the calpain and caspase
pathways in demyelination and neurodegeneration in experimental
autoimmune encephalomyelitis (EAE), which is a widely used
animal model of MS. Supposedly, EAE exhibits many similarities
with MS and as such it is a highly useful animal model for
understanding both the mechanisms of immune-mediated CNS pathology
and also the progressive clinical course of MS. Although demyelination
and axonal dysfunction are well characterized in EAE and MS,
current evidences strongly suggest occurrence of axonal damage
and neuronal death as well. Recent studies demonstrate the
activation of calpain and caspase pathways that contribute
to apoptotic death of both oligodendrocytes and neurons in
EAE and thereby amplify the pathological events leading to
neurological deficits. Apoptosis occurs in the disease-initiation
as well as in the disease-promotion phases in EAE. This review
article highlights the major contributions of calpain and
caspase pathways to demyelination and neurodegeneration in
EAE animals and thereby suggests use of inhibitors of these
proteases to prevent demyelination and neurodegeneration.
Current volume of the CNS & Neurological Disorders
– Drug Targets is a collection of all interesting
review articles from the experts who have critically evaluated
and described the roles of some of the proteases and also
phospholipases in the pathogenesis of a wide variety of CNS
disorders. Therapeutic interventions using the inhibitors
of proteases and phospholipases have already shown promising
results in the pre-clinical models of CNS injuries and diseases
[3, 7, 9, 10]. It is enthusiastically expected that our ever
increasing understanding of the pathogenic roles of different
proteases and phospholipases is going to help us in rational
design of the targeted therapeutic agents for the treatment
many CNS disorders in the future.
REFERENCES
[1] Bartus, R.T.; Elliott, P.J.; Hayward, N.J.; Dean, R.L.;
Harbeson, S.; Straub, J.A.; Li, Z.; Powers, J.C. Neurol.
Res., 1995, 17, 249-258.
[2] Yakovlev, A.G.; Faden, A.I. Mol. Neurobiol.,
2001, 24, 131-144.
[3] Ray, S.K.; Banik, N.L. Curr. Drug Targets CNS Neurol.
Disord., 2003, 2, 173-189.
[4] Prunell, G.F.; Arboleda, V.A.; Troy, C.M. Curr. Drug
Targets CNS Neurol. Disord., 2005, 4,
51-61.
[5] Röcken, C.; Fändrich, M.; Stix, B.; Tannert,
A.; Hortschansky, P.; Reinheckel, T.; Saftig, P.; Kähne,
T.; Menard, R.; Ancsin, J.B.; Bühling, F. J. Pathol.,
2006, 210, 478-487.
[6] Sun, G.Y.; Xu, J.; Jensen, M.D.; Simonyi, A. J. Lipid
Res., 2004, 45, 5-13.
[7] Ray, S.K.; Hogan, E.L.; Banik, N.L. Brain Res. Rev.,
2003, 42, 169-185.
[8] Farooqui, A.A.; Ong, W.Y.; Horrocks, L.A. Pharmacol.
Rev., 2006, 58, 591-620.
[9] Reid, R.C. Curr. Med. Chem., 2005,
12, 3011-3026.
[10] Ray, S.K. Curr. Med. Chem., 2006,
13, 3425-3440.
Swapan K. Ray
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine
6439 Garners Ferry Road
Building 2, Room C11
Columbia, SC 29209
USA
Email: raysk8@gw.med.sc.edu
[Back to top]
Therapeutic Strategy of Erythropoietin in Neurological
Disorders
Xiang-Bao Liu, Jiang-An Wang, Shan Ping
Yu, Christine L. Keogh and Ling Wei
Erythropoietin (EPO) was first identified as a hematopoietic
cytokine that stimulates proliferation and differentiation
of erythroid progenitor cells and was approved by the Food
and Drug Administration as a treatment for chronic renal disease
patients with anemia. In neural tissues, EPO is working via
EPO receptors and induces non-hematopoietic effects. Recent
studies have demonstrated that EPO exerts therapeutic potentials
on neurological disorders such as ischemic stroke, intracerebral
hemorrhage, subarachnoid hemorrhage, traumatic brain injury,
and Parkinson's disease. EPO treatment has been shown to reduce
the ischemic infarct and hemorrhage volume, decrease neuronal
death including apoptosis, and improve survival rates in animal
models. The mechanism of EPO action in neurological disorders
involves neuroprotection and promotion of neurogenesis and
angiogenesis. Clinical trials of EPO treatments in neurological
diseases have accumulated positive results. In stroke patients,
EPO treatment may reduce infarct volume and improve functional
outcomes. EPO administration has proven safe in animal studies
and adult human patients, although safety and efficacy data
in neonates and infants are incomplete and long-term multi-center
patient evaluations are necessary. Available information suggests
that EPO is a promising therapeutic drug for the treatment
of neurological diseases.
[Back to top]
Targeting Extracellular Matrix Proteolysis for Hemorrhagic
Complications of tPA Stroke Therapy
Xiaoying Wang, Anna Rosell and
Eng H. Lo
To date, tPA-based thrombolytic therapy is the only FDA-approved
treatment for achieving vascular reperfusion and clinical
benefit, but this agent is given to only about 2-5% of stroke
patients in the United States of America. This may be related,
in part, to the elevated risks of symptomatic intracranial
hemorrhage, and the consequently reduced therapeutic time
window. Recent efforts have aimed at identifying new combination
strategies that might increase thrombolytic efficacy of tPA
to benefit reperfusion, while reducing its associated neurotoxicity
and hemorrhagic complications. Emerging experimental studies
demonstrate that the breakdown of neurovascular matrix initiates
blood–brain barrier disruption with edema and/or hemorrhage.
Perturbation of extracellular homeostasis triggered by dysregulated
extracellular proteases may underlie processes responsible
for the hemorrhagic complications of thrombolytic stroke therapy.
This short review summarizes experimental investigations of
this field in pre-clinical stroke models. The data strongly
suggest that targeting the extracellular matrix proteolytic
imbalance within the neurovascular unit may provide new approaches
for improving the safety and efficacy of thrombolytic reperfusion
therapy of stroke.
[Back to top]
Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases
in the Pathogenesis of Stroke: Therapeutic Strategies
Rao Muralikrishna Adibhatla and James
F. Hatcher
Today there exists only one FDA-approved treatment for
ischemic stroke; i.e., the serine protease tissue-type plasminogen
activator (tPA). In the aftermath of the failed stroke clinical
trials with the nitrone spin trap/radical scavenger, NXY-059,
a number of articles raised the question: are we doing the
right thing? Is the animal research truly translational in
identifying new agents for stroke treatment? This review summarizes
the current state of affairs with plasminogen activators in
thrombolytic therapy. In addition to therapeutic value, potential
side effects of tPA also exist that aggravate stroke injury
and offset the benefits provided by reperfusion of the occluded
artery. Thus, combinational options (ultrasound alone or with
microspheres/nanobubbles, mechanical dissociation of clot,
activated protein C (APC), plasminogen activator inhibitor-1
(PAI-1), neuroserpin and CDP-choline) that could offset tPA
toxic side effects and improve efficacy are also discussed
here. Desmoteplase, a plasminogen activator derived from the
saliva of Desmodus rotundus vampire bat, antagonizes
vascular tPA-induced neurotoxicity by competitively binding
to low-density lipoprotein relatedreceptors (LPR) at the blood-brain
barrier (BBB) interface, minimizing the tPA uptake into brain
parenchyma. tPA can also activate matrix metalloproteinases
(MMPs), a family of endopeptidases comprised of 24 mammalian
enzymes that primarily catalyze the turnover and degradation
of the extracellular matrix (ECM). MMPs have been implicated
in BBB breakdown and neuronal injury in the early times after
stroke, but also contribute to vascular remodeling, angiogenesis,
neurogenesis and axonal regeneration during the later repair
phase after stroke. tPA, directly or by activation of MMP-9,
could have beneficial effects on recovery after stroke by
promoting neurovascular repair through vascular endothelial
growth factor (VEGF). However, any treatment regimen directed
at MMPs must consider their pleiotropic nature and the likelihood
of either beneficial or detrimental effects that might depend
on the timing of the treatment in relation to the stage of
brain injury.
[Back to top]
Role of Secretory Phospholipase A2
in CNS Inflammation: Implications in Traumatic Spinal Cord
Injury
W. Lee Titsworth1, Nai-Kui Liu and
Xiao-Ming Xu
Secretory phospholipases A2
(sPLA2s) are a subfamily
of lipolytic enzymes which hydrolyze the acyl bond at the
sn-2 position of glycerophospholipids to produce
free fatty acids and lysophospholipids. These products are
precursors of bioactive eicosanoids and platelet-activating
factor (PAF). The hydrolysis of membrane phospholipids by
PLA2 is a rate-limiting step
for generation of eicosanoids and PAF. To date, more than
10 isozymes of sPLA2 have
been found in the mammalian central nervous system (CNS).
Under physiological conditions, sPLA2s
are involved in diverse cellular responses, including host
defense, phospholipid digestion and metabolism. However, under
pathological situations, in-creased sPLA2
activity and excessive production of free fatty acids and
their metabolites may lead to inflammation, loss of membrane
integrity, oxidative stress, and subsequent tissue injury.
Emerging evidence suggests that sPLA2
plays a role in the secondary injury process after traumatic
or ischemic injuries in the brain and spinal cord. Importantly,
sPLA2 may act as a convergence
molecule that mediates multiple key mechanisms involved in
the secondary injury since it can be induced by multiple toxic
factors such as inflammatory cytokines, free radicals, and
excitatory amino acids, and its activation and metabolites
can exacerbate the secondary injury. Blocking sPLA2
action may represent a novel and efficient strategy to block
multiple injury pathways associated with the CNS secondary
injury. This review outlines the current knowledge of sPLA2
in the CNS with emphasis placed on the possible roles of sPLA2
in mediating CNS injuries, particularly the traumatic and
ischemic injuries in the brain and spinal cord.
[Back to top]
New Insights into the Roles of Endolysosomal Cathepsins
in the Pathogenesis of Alzheimer’s Disease: Cathepsin
Inhibitors as Potential Therapeutics
Azizul Haque, Naren L. Banik and Swapan
K. Ray
Endolysosomal proteases such as cysteinyl and aspartyl
cathepsins play diverse roles in inflammatory autoimmune diseases,
cancers, and neurodegenerative diseases. Cysteinyl cathepsin
B and aspartyl cathepsin D levels are markedly elevated in
a variety of neurological disorders including Alzheimer’s
disease (AD), a leading cause of dementia in the elderly.
Studies have also shown an increased cathepsin activity in
AD patients where senile plaques and neuronal loss are marked
features of the disease. Senile plaques contain amyloid-beta
(Aβ)
peptide, which is produced by proteolytic cleavage of the
amyloid precursor protein (APP) by the proteases. In this
article, we present the current knowledge of cysteinyl and
aspartyl cathepsins in cellular and molecular events that
lead to formation of senile plaques in AD. This article also
focused on the role of cathepsin inhibitors as disease-modifying
treatment strategies that could halt, or even prevent, this
devastating neurological disorder.
[Back to top]
Beta-Secretase: Structure, Function, and Evolution
Chitra Venugopal, Christina M. Demos, K.S.
Jagannatha Rao, Miguel A. Pappolla and Kumar Sambamurti
The most popular current hypothesis is that Alzheimer’s
disease (AD) is caused by aggregates of the amyloid peptide
(Aβ),
which is generated by cleavage of the Aβ
protein precursor (APP) by β-secretase
(BACE-1) followed by γ-secretase.
BACE-1 cleavage is limiting for the production of Aβ,
making it a particularly good drug target for the generation
of inhibitors that lower Aβ.
A landmark discovery in AD was the identification of BACE-1
(a.k.a. Memapsin-2) as a novel class of type I transmembrane
aspartic protease. Although BACE-2, a homologue of BACE-1,
was quickly identified, follow up studies using knockout mice
demonstrated that BACE-1 was necessary and sufficient for
most neuronal Aβ
generation. Despite the importance of BACE-1 as a drug target,
development has been slow due to the incomplete understanding
of its function and regulation and the difficulties in developing
a brain penetrant drug that can specifically block its large
catalytic pocket. This review summarizes the biological properties
of BACE-1 and attempts to use phylogenetic perspectives to
understand its function. The article also addresses the challenges
in discovering a selective drug-like molecule targeting novel
mechanisms of BACE-1 regulation.
[Back to top]
Neuroprotection in Glaucoma Using Calpain-1
Inhibitors: Regional Differences in Calpain-1 Activity in
the Trabecular Meshwork, Optic Nerve and Implications for
Therapeutics
Bharathi Govindarajan, James Laird, Ronald Sherman,
Robert G. Salomon and Sanjoy K. Bhattacharya
Glaucoma is a group of irreversible blinding eye diseases
affecting over 70 million people worldwide. Systemic delivery
of calpain-1 inhibitors was proposed as a neuroprotection
strategy for the prevention of progressive optic nerve damage
in glaucoma. We present a general review of calpain-1 and
an account of vast differences in processing of calpain-1
in the trabecular meshwork (TM) and the optic nerve. Calpain-1
accumulates in the glaucomatous TM tissues in vivo.
However, calpain-1 activity is substantially lower in the
glaucomatous TM compared to controls, apparently owing to
partial degradation, and modification by lipid oxidation products
such as iso [4]levuglandin E2 (iso [4]LGE2). Treatment of
calpain-1 with iso [4]LGE2
in vitro results in covalent modification, inactivation,
and resistance to protease digestion. Iso [4]LGE2-modified
calpain-1 appeared to undergo ubiquitination in the TM by
cellular degradation machinery mediated by ubch1-2, ubch5,6
and E6-AP, E2 and E3 enzymes respectively. In the TM, iso
[4]LGE2-modified calpain-1
loading impairs the cellular proteasome activity consistent
with competitive inhibition and formation of suicidal high
molecular weight aggregates. In contrast, higher calpain-1
activity, that appears to be under translational control,
was observed in glaucomatous optic nerve compared to control.
Therapeutic neuroprotection strategies using calpain-1 inhibitors
will require consideration of such anatomic differences in
its activity and biosynthesis.
[Back to top]
Calpain as a Potential Therapeutic Target in Parkinson’s
Disease
Supriti Samantaray, Swapan K. Ray and
Naren L. Banik
Pathophysiology of idiopathic Parkinson’s disease
(PD) is associated with degeneration of dopaminergic neurons
and inflammatory responses in the mid-brain substantia nigra
(SN). However, central dopaminergic replenishment therapeutic
strategy with L-3,4-dihydroxyphenylalanine (L-DOPA), the precursor
for dopamine synthesis, does not fully rescue these cells
in SN or improve motor function. Besides, prolonged use of
L-DOPA worsens the clinical symptoms in PD patients. Thus,
there is a possibility that other areas of central nervous
system may also be affected in this disease. Spinal cord,
the final coordinator of movement in the central nervous system,
may be one such site that is critically affected during pathogenesis
of this complex movement disorder. In this review, we summarize
the evidence in support of involvement of calpain, a Ca2+-activated
non-lysosomal protease, in spinal cord degeneration in two
models of experimental parkinsonism induced by the neurotoxin
1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine and also the
environmental toxin rotenone. The key focus of this review
is to discuss the role that calpain plays in disrupting the
structural and functional integrity of the spinal cord in
these experimental models of parkinsonism. A similar disruptive
role of calpain has been reported earlier in SN of PD patients
as well as in experimental PD animals. Studies in rodent and
cell culture models of PD suggest that treatment with calpain
inhibitors (e.g., calpeptin, MDL-28170) can prevent neuronal
death and restore functions. Furthermore, the degradation
of calpain substrates in both brain and spinal cord during
pathogenesis of PD suggested a putative role of calpain, and
calpain inhibition as a therapeutic strategy in PD.
[Back to top]
Activation of Calpain and Caspase Pathways in Demyelination
and Neurodegeneration in Animal Model of Multiple Sclerosis
Arabinda Das, M. Kelly Guyton, Jonathan
T. Butler, Swapan K. Ray and Naren L. Banik
Experimental autoimmune encephalomyelitis (EAE), a widely
recognized animal model of multiple sclerosis (MS), is highly
useful for studying inflammation, demyelination, and neurodegeneration
in the central nervous system (CNS). EAE exhibits many similarities
with MS, which is a chronic inflammatory disease affecting
CNS white matter in humans. Various studies have indicated
that EAE is a particularly useful animal model for understanding
both the mechanisms of immune-mediated CNS pathology and also
the progressive clinical course of MS. Demyelination and axonal
dysfunction have previously been shown in MS and EAE but current
evidences indicate that axonal damage and neuron death also
occur, demonstrating that these diseases harbor a neurodegenerative
component. Recent studies also have shown that the activation
of calpain and caspase pathways contribute to the apoptotic
death of oligodendrocytes and neurons, promoting the pathological
events leading to neurological deficits. Apoptosis is involved
in the disease-regulating as well as in the disease-promoting
processes in EAE. This review discusses the major involvement
of calpain and caspase pathways in causing demyelination and
neurodegeneration in EAE animals.
|
