Neurotrophic Factors Presentation.pptx

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1. NEUROTROPHIC FACTORS Presented by: Dr. Akul Gupta Junior Resident Department of Psychiatry Teerthanker Mahaveer Medical College and Research Centre

2. History

3. Introduction Neurotrophins are a unique family of polypeptide growth factors that influence proliferation, differentiation, survival, death of neuronal and nonneuronal cells. The effects of neurotrophins depend upon their Levels of availability, Affinity of binding to transmembrane receptors, The downstream signaling cascades.

4. Neurotrophin Family

5. Biosynthesis of Neurotrophic Factors Proneurotrophins Cleaved Intracellularly Extracellularly By Furin or Proconverteases By Plasmin or Matrix Metalloproteases Mature Proteins Bind to Tyrosine Kinase Receptor (TrK) p75 Neurotrophin Receptor (p75 NTR ) Regulate neuronal survival, differentiation, and synaptic plasticity. Modulate affinity of TrK neurotrophin associations.

6. Neurotrophin receptors Neurotrophins are unique in exerting their cellular effects through the actions of two different receptors : Trk receptor Trk receptors consist of an extracellular ligand-binding region, a single transmembrane domain, and a highly conserved intracellular tyrosine kinase domain. p75 NTR receptor The p75 NTR receptor consists of an extracellular ligand binding region, a single transmembrane domain, and an intracellular portion containing a protein-association region termed the death domain There are no sequence similarities between Trk and p75 receptors in their either ligand binding or cytoplasmic domains.

7. Neurotrophin receptor signaling

8. Neurotrophin binding specificities

9. The Neurotrophin Hypothesis It states that neurons compete for limited quantities of neurotrophins in target regions, which leads to selective neuronal survival . Levels of target derived neurotrophins and neurotrophin receptors will determine efficacy of survival and responsiveness of the neurons. The ability to form high-affinity binding sites allows for greater responsiveness under limiting quantities of trophic factors. Lack of trophic support or incorrect targeting of axons to the wrong target results in programmed cell death .

10. Neurotrophic factors and development Two predictions emanate from the neurotrophic hypothesis: First, the efficacy of neuronal survival will depend upon the amounts of trophic factors produced during development. Second, specific receptor expression in responsive cell populations will dictate neuronal responsiveness . It is clear now that neurons can release neurotrophins that act on themselves ( autocrine transmission ) or can be anterogradely transported down axons and act on neighboring neurons.

11. Neurotrophins promote cell survival and differentiation during neural development. Paradoxically, they can also induce cell death . p75 NTR serves as a proapoptotic receptor during developmental cell death and after injury to the nervous system. The biological action of the neurotrophins can be regulated by proteolytic cleavage , with pro-forms preferentially activating p75 NTR to mediate apoptosis and mature forms selectively activating Trk receptors to promote survival . Neurons must establish connections with the proper target. In the event of mistargeting , neurons may undergo apoptosis if the appropriate set of trophic factors or receptors is not encountered.

12. Axonal transport Specificity of the biological effects of neurotrophins can also be modulated by the intracellular location of the neurotrophin ligand receptor complex . A central theme of the neurotrophic hypothesis is that neuronal survival and differentiation depend upon the retrograde signaling of trophic factors produced at the target tissue. Each neurotrophin binds to transmembrane receptors and undergoes internalization and transport from axon terminals to neuronal cell bodies. Both Trk and p75 NTR receptors undergo retrograde transport. The term “signaling endosome” has been coined to describe membrane vesicles that carry Trk , p75 NTR , and NGF.

13. Neurotrophins and synaptic plasticity Recent studies have established that neurotrophic factors play significant roles in influencing synaptic plasticity and modulating neuronal activity in the adult brain. Developmental regulation of synaptic plasticity in the visual system is illustrated by the formation of ocular dominance columns in layer 4 of the cortex, which can be strongly influenced by exogenous neurotrophins such as BDNF. Modulation of synaptic plasticity in the differentiated adult brain has also been demonstrated in the hippocampus in a series of studies. Neurotrophins like exogenous BDNF or NT-3 have also been shown to evoke other forms of synaptic transmission in both hippocampal preparations and neuromuscular junctions .

14. Neurotrophins and behaviour A recent series of studies on genetically modified mice with reduced levels of BDNF have indicated striking effects upon adult brain function and behavior . Mice with reduced BDNF levels exhibit enhanced aggressiveness , hyperactivity , and hyperphagia . ICV infusion of BDNF or NT-4 led to a striking reversal of the feeding phenotype. Also, serotonergic neuronal functioning was abnormal in the forebrain, cortex, hippocampus, and hypothalamus. On administration of fluoxetine, an SSRI, the aggressive behavior, hyperphagia, and hyperlocomotor activity were ameliorated.

15. This study and other conditional BDNF mice demonstrated that the feeding phenotype and the other behavioral abnormalities were mediated by the functioning of BDNF in the CNS as compared to any peripheral actions of the neurotrophin. Abnormal behaviors elicited by partial deletion of BDNF indicate a significant role for this neurotrophin in higher-order behaviors, which have clinical correlates to psychiatric disorders , especially those associated with alteration in central serotonergic functioning .

16. Other neurotrophic factors Glial-derived neurotrophic factor (GDNF) is one of the most potent trophic factors for dopaminergic neurons and has shown to maintain the survival of dopaminergic neurons in the midbrain as well as neurons in the myenteric plexus in the gut. Due to its trophic effects on dopaminergic neurons, it has been considered a potential therapeutic agent for Parkinson disease. Ciliary neurotrophic factor (CNTF) maintains the survival of ciliary neurons as well as motor neurons. CNTF has been investigated as a therapeutic agent for motor neuron diseases such as ALS.

17. Clinical significance Neurotrophic factors regulate numerous neuronal functions in development, adult life and in response to injury. Few human diseases affecting the nervous system have been shown to be caused by a defect in the neurotrophins or their receptors . Modulation of neuronal survival and axonal growth was the initial rationale for potential clinical correlates to Alzheimer disease, Parkinson disease, HD, and ALS as well as spinal cord injury . The additional effects of neurotrophic factors on synaptic connections, synaptic plasticity, and neurotransmission have formed the basis for their association with psychiatric disorders such as depression and substance abuse .

18. The hypothesis underlying these clinical and therapeutic correlations assumes that these disease states result in either: Decreased availability of neurotrophins for the affected neurons, Decreased number of neurotrophin receptors on the affected neurons, and/or Decreased neuronal survival . These deficits can be ameliorated by the addition of neurotrophic factors. For example in Huntington’s disease , which is characterized by progressive death of medium spiny neurons in the striatum, the pathogenic effects of mutant huntingtin protein are explained through a decrease in BDNF levels brought on by lower anterograde transport from the cortex to the striatum. In Alzheimer disease , addition of ICV NGF or BDNF to vulnerable regions of the brain, such as the entorhinal cortex or hippocampus , can increase spatial learning and memory retention. Thus, exogenous neurotrophic factors could provide symptomatic treatment , rather than a cure for the core pathophysiology of these nervous system disorders.

19. Neurodegenerative disorders The initial clinical correlation to Alzheimer disease was made in the 1980s Animal studies showed that cholinergic neurons in the basal forebrain could be rescued with NGF , resulting in concomitant improvements in memory function . In motor neuron degeneration, BDNF and CNTF showed increase in the number of motor neurons and improved motor performance. These studies led to the therapeutic strategy to attempt to treat degenerative diseases with neurotrophins.

20. In the 1990s, great effort was focused on studying whether neurotrophic factors could be used as a treatment strategy for ALS. Subcutaneous or intrathecal delivered BDNF, CNTF, and NGF had minimal beneficial effect and was associated with side effects such as fever, pain, anorexia and gastrointestinal symptoms. Recent studies and g ene expression profiling suggest that striatal-specific atrophy in HD may be a consequence of a decrease in cortical BDNF by mutant huntingtin. Although clinical trials have been disappointing, there is growing evidence that several specific neurodegenerative diseases would benefit if we can deliver adequate quantities of neurotrophins to CNS without peripheral side-effects .

21. Significance in Psychiatric Disorders The profound effects of neurotrophic factors on synaptic connections, synaptic plasticity, and neurotransmission have formed the basis for their association with psychiatric disorders, such as anxiety disorders, depression, and substance abuse . It has become clear that neurotrophins can produce long-term changes by regulating transcriptional programs on the functioning of adult neurons. The strongest evidence for a role of neurotrophins has come from the pathophysiology of depression , especially those associated with stress.

22. Major Depressive Disorder There are several lines of evidence suggesting a role of neurotrophins in depression. Structural remodeling (decrease in hippocampal volume) and synaptic plasticity involved in the cellular pathophysiology of depression make BDNF an attractive candidate molecule to mediate these alterations. Exogenous BDNF in the hippocampus had antidepressant effects in animal models of depression similar to chronic treatment with pharmacological antidepressants.

23. SSRIs & SNRIs upregulate CREB and BDNF in a time course that corresponds to therapeutic action (10 to 20 days). Two other antidepressant treatments, MAOIs and ECT , upregulate BDNF transcription. Ketamine could also mediate a rapid antidepressant response through a BDNF-dependent mechanism. Conversely, exogenously administered BDNF in the mesolimbic dopamine system appears to have an opposite effect — increasing depression-like behavior. Removal of BDNF in this dopamine circuit appears to have antidepressant effects on a social defeat paradigm. These studies provide a framework to examine further the neurotrophin system as a potential therapeutic target for the treatment of depression.

24. Other psychiatric disorders PSYCHIATRIC DISORDERS NEUROTROPHIC FACTORS Bipolar Affective Disorder Decreased BDNF Lithium & Valproate increase BDNF in the corticolimbic pathway Anxiety BDNF increases the susceptibility to stress and anxiety Schizophrenia Mixed results Substance Abuse Increased BDNF -> LTP & synaptic plasticity -> increased drug seeking behaviour

25. Neurotrophins and Genetics A single nucleotide polymorphism (SNP) in the BDNF gene is related to psychiatric disorders. SNP leads to a single amino acid change from valine (Val) to methionine (Met) at position 66 in BNDF gene resulting in improper folding of BDNF protein. This causes greater risk of bipolar affective disorder, schizophrenia, depression and anxiety. This polymorphism is common with an allele frequency of 20-30 %. Humans that are heterozygous for the Met allele have Smaller hippocampal volumes Perform poorly on hippocampal dependent memory tasks.

26. Future directions Physical delivery of sufficient quantities to target neurons by development of small molecules that readily cross the BBB to activate or potentiate the actions of neurotrophins is an approach that is in its infancy. New strategies for local and regulated application of neurotrophins through stereotactic injection of viral vectors or engineered progenitor cells . The activation of the neurotrophin system through other receptor signalling systems like small molecules that elicit neurotrophic effects for the treatment of neurodegenerative diseases by selective targeting of neurons that express specific GPCRs and Trk receptors. Further understanding of the core pathophysiological mechanism for neurodegenerative and psychiatric disorders will benefit the development of rational therapies that involve engaging the neurotrophin system .

27. Summary Neurotrophic factors are polypeptide growth factors influencing proliferation, differentiation, survival & death of neuronal and nonneuronal cells Expansion in the research during the last 20 years, sparked by the discovery of BDNF has lead to their implication in pathophysiology of mood disorders Prospect of neurotrophic factors being used in the clinical therapy of neurodegenerative disorders remains uncertain. With the inability to cross BBB, treatment strategies, similar to antidepressants which enhance or support the synthesis or release of endogenous neurotrophic factors, are likely to become widespread in the future.