ANXIETY, DEPRESSION AND NEURODEGENERATIVE DISEASES: NOVEL RESULTS IN THE DISCOVERY OF THEIR PATHOMEC

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ANXIETY, DEPRESSION AND NEURODEGENERATIVE
DISEASES NOVEL RESULTS IN THE DISCOVERY OF THEIR
PATHOMECHANISMS AND NOVEL DRUG CANDIDATES

• Botond Penke
• University of Szeged
• September 25, 2008.

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NEUROBIOLOGICAL KNOWLEDGE CENTER (NBKC) OF THE
SZEGED REGION
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THE MEMBERS OF THE CONSORTIUM
President of SNKC Prof. Gyula Telegdy

• University of Szeged
• Biological Research Center of Szeged of the
  Hungarian Academy of Science
• Hungarian Academy of Science Supported Research
  Groups
• EGIS Pharmaceuticals
• SOLVO Biotechnology Inc.
• Diagnosticum Inc.
• Kromat Ltd.
• Creative Labor Ltd.
• Rytmion RD Ltd
• Kation Europe
• QualiCont In Vitro Diagnostics
• South-Plain Bioinnovation Center, Genomic
  Laboratory

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RUNNING PROJECTS OF THE NBKC-SZEGED

• Pathomechanisms of neurodegenerative diseases
• Novel drugs for prevention and treatment of
  Alzheimers and Parkinsons disease (Patent
  application, PCT)
• (Peptidomimetics)
• Early diagnosis of Alzheimers disease (AD)
• Anxiety and depression
• Novel drugs for prevention and treatment of
  these syndromes
• Neuroproteomical studies validation of target
  proteins
• Development of new diagnostics
• Tc-labeled novel diagnostics (AD)
• Early diagnosis of prion diseases
• New diagnostics for neuromuscular diseases
• Novel diagnostic methods of psychiatric diseases
  using gene expression
• Differential diagnosis of sclerosis multiplex
  subtypes

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RESEARCH LABORATORIES AND FACILITIES IN THE NBKC
(2008)

• High performance computer facility
• Laboratories for organic syntheses
• a, Peptides and peptidomimetics
• b, Heterocyclic compounds and DNA/RNA oligos
• NMR Laboratory (500 and 600 MHz)
• Cell and tissue culture laboratory
• Electrophysiology laboratory
• Learning and behaviour laboratory
• Proteomics facility
• Animal house (rats, mice)
• (Molecular biology laboratory)

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THE PROGRESS OF AGEING
AGEING IS THE RESULT OF ALTERATIONS, MUTATIONS,
DETERIORATIONS IN THE MACROMOLECULES (NUCLEIC
ACIDS, PROTEINS, LIPIDS) OF THE CELL. AGEING IS A
CONSEQUENCE OF THESE PROCESSES.
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DISEASES COMING WITH AGEING
Tumor diseases
Diabetes
90 year
60
30
Woman
Arteric hipertonia
Alzheimer disease
Alzheimer kór
Man
60
90 year
60
90 year
30
30
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Ventricle
Normal
Alzheimers
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Aß-LEVEL IN THE CSF
fAb42
Normal CSF
1. patient
2. patient
3. patient
10
20
30
40
50
60
70
month
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PET STUDIES NORMAL AND AD-BRAIN
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THE CONSENSUS HYPOTHESIS OF THE ETIOPATHOLOGY OF
ALZHEIMERS-DISEASE

• Central role of
• - Disturbances of the brain circulation
• - The state/quality of the brain capillaries
• - Deterioration of neurons in the association
  cortex
• Phases
• 1, Chronic hypoxia, hypoglycemia) capillary
  degeneration in the water shed of the brain
  -neurodegeneration
• 2, Free radical formation, Ca2-influx, APP, Aß42
  
• -neuronal death in the entorhinális cortex
• 3, Increasing Aß level, tau-hyperphosphorylation
• -neuronal death in the hippocampus, gyrus
  dentatus, neurofibrillary tangles

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Aß PROTEIN INTERACTIONS
PKA protein kináz A ERK extra cell. signal reg.
kináz CREB cAMP response element protein DGL
diacilglic. lipáz PI3K foszf. inocit
3-kináz PKC protein kináz C Akt protein kináz
B mTOR mamm. Translation of rapamycin 2AG
endokannabinoid arach. Glicerin CB1 kannabinoid
receptor MEK mitogén akt. protein kináz PLC
foszfolipáz C GSK3 glikogén szintáz kináz 3 DAG
diacil glicerin CaMKII calcium/calmodulin
dependens protein kináz II
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RISK FACTORS OF ALZHEIMERS DISEASE

• 1, Genetic factors APP, PS1 mutations (0,3)
• ApoE e4 mutant allele (15)
• 2, Hypoxia
• 3, Hypoglycemia
• 4, Cardivascular diseases
• 5, Untreated hypertension
• 6, Brain damages (dementia pugilistica)
• 7, High cholesterol level in cell membrane
• 8, Neurotoxins (3-OH-kinurenin,
  ß-methylamino-alanin)
• 9, The ageing process itself
• (low estradiol and testosterone level
• decreased activity of repair mechanizms)

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PREVENTION, DRUG TREATMENT THERAPEUTIC WINDOW
severity
year
80
50
55
60
65
70
75
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TARGETS THE DRUG DESIGN FOR TREATMENT OF
ALZHEIMER-DISEASE
1. APP and ß g secretase inhibitors Do not
form Aß42! 2. ßsheet breakers, BSB Do not
aggregate Aß42! 3. Inhibitors of the interaction
between Aß42 and membranes - Amyloid surface
binding molecules - Competitive inhibitors (RGD
peptides?) - Memantine /NMDA 4. Kinase
inhibitors Do not hyperphosphorylate tau! 5.
Anti inflammatory drugs microglia
inactivation 6. Cholinesterase inhibitors 7.
Immunization - Aß clearance from the brain
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BIOLOGICAL STUDIES OF DRUG CANDIDATES FOR
ALZHEIMERS DISEASEHit compound
Leu-Pro-Tyr-Phe-Asp-NH2

• IN VITRO STUDIES
• 1. MTT-TEST
• 2. MEASUREMENT OF Ca2-AFFLUX
• 3. EX VIVO ELECTROPHYSIOLOGY ON BRAIN SLICES
• IN VIVO STUDIES
• 1. ELECTROPHYSIOLOGY, ONE-CELL/MULTIBARREL
  ELECTRODE, MULTI ARRAY ELECTRODE, RAT
  HIPPOCAMPUS
• 2. LEARNING AND BEHAVIOR
• OBJECT RECOGNITION
• MORRIS WATER MAZE
• CROSS MAZE

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NOVEL PEPTIDOMIMETICS, NOVEL MECHANISM LPYFDa is
not BSB, but iniciate the formation of
superaggregates
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DRUG DEVELOPMENT FOR TREATING ALZHEIMERS
DISEASE NOVEL DRUG CANDIDATES

• OPTIMIZING THE ASBIM-LEAD, 72 NEW PEPTIDOMIMETICS
  WERE SCREENED (IN VITRO AND IN VIVO).
• 3 COMPOUNDS WERE SELECTED FOR FURTHER DRUG
  DEVELPMENT P29, P59, P79.
• THESE COMPOUNDS WERE ABSORBED FROM THE GUT
• THESE COMPOUNDS PASS ACROSS BBB
• THESE COMPOUNDS ARE NON TOXIC IN MICE (28 DAYS,
  100mg/kg)
• P59 AND P79 ARE RESISTANT AGAINST PROTEASES
• ORGAN DISTRIBUTION OF P29 AND P59 WERE MEASURED
  USING TRITIATED COMPOUNDS
• P59 IN VIVO PROTECTS RATS AGAINST THE MEMORY
  DISTURBING EFFECT OF Aß 1-42 OLIGOMERS
  (MICROINJECTION INTO THE ENTORHINAL CORTEX
  MORRIS WATER MAZE SPATIAL MEMORY)

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