Neurotrophins, Neurogenesis, and Depression

Neurotrophins Help Nerve Cells Develop, Function, and Survive

Natural brain neurotrophins can encourage neurogenesis, as well as helping to guide neurons to their proper locations in the brain, helping them make functional connections, and promoting their survival under certain adverse conditions.

The first neurotrophin, NGF [Nerve Growth Factor], was isolated from snake venom as early as 1956 based on its ability to promote the neurite growth of sympathetic neurons in chicken (Cohen and Levi-Montalcini, 1956). NGF prevented the neuronal death caused by 6-hydroxydopamine (6-OHDA) (Levi-Montalcini et al., 1975), vinblastine or surgical transectomy (Hendry 1975) of the postganglionic axons of the superior cervical ganglion. The ability of neurons to grow axons towards increasing concentrations of NGF (Gundersen and Barrett, 1979; Gundersen and Barrett, 1980) finally led to the target field hypothesis of the development of innervation. This theory (Korsching 1993; Lewin and Barde, 1996) postulates that, as most of the developing neurons die during embryogenesis, their survival is dependent on the ability of the neuron to compete for the limited amount of a trophic factor. Those neurons that fail to grow axons to the target then die apoptotically…

Table1. Neurotrophic factor families 
Neurotrophins

  • Nerve Growth Factor (NGF)
  • Brain Derived Neurotrophic Factor (BDNF)
  • Neurotrophin 3 (NT3)
  • Neurotrophin 4/5 (NT4/5)
Neuropoietins

  • Ciliary Neurotrophic Factor (CNTF)
  • Leukemia Inhibitory Factor (LIF)
Insulin-like Growth Factors 1-2 (IGF-1, IGF-2)
Transforming Growth Factors

  • Transforming Growth Factor a (TGFa )
  • Transforming Growth Factor b 1-3 (TGFb 1, TGFb 2, TGFb 3)
  • Glial Cell Line-Derived Neurotrophic Factor (GDNF)
  • Neurturin (NTN)
  • Persephin (PSP)
Fibroblast Growth Factors

  • Acidic Fibroblast Growth Factor (FGF-1)
  • Basic Fibroblast Growth Factor (FGF-2)
  • Fibroblast Growth Factor-5 (FGF-5)
Other factors

  • Platelet-Derived Growth Factor (PDGF)
  • Stem Cell Factor (SCF)

  __ Source

(More from Wikipedia on Neurotrophins)

Beyond the natural neurotrophins, scientists are developing synthetic neurogenic compounds to be used in treating severe, treatment-resistant depression, and for treating cognitive deficits from nerve/brain damage of various types. One such compound — NSI-189 [Neuralstem Inc.] — recently came through phase 1-B clinical trials in the US, demonstrating both safety and efficacy.

A small clinical trial of a novel antidepressant that stimulates neurogenesis — the production of new brain cells — shows that the compound appears to be safe and may be effective against depression. Results of the phase 1B trial, led by Massachusetts General Hospital (MGH) investigators, show that treatment with the drug currently identified as NSI-189 improved both depressive and cognitive symptoms in study participants and that its effects appear to persist for several months after treatment discontinuation. The study was supported by the pharmaceutical company Neuralstem. __ http://www.sciencedaily.com/releases/2015/12/151208081321.htm

Full study in Nature Molecular Psychiatry

It has been known for several years that neurogenesis in adult humans can accompany long-term treatment with antidepressant drugs:

The mechanisms underlying the regulation of hippocampal neurogenesis are being actively investigated. Interestingly, both the cAMP cascade and BDNF, which we have found to be upregulated by antidepressant treatment (Nibuya et al., 1995, 1996; Thome et al., 2000), have been shown to play a role in the regulation of neurogenesis. Activation of the cAMP pathway or incubation with BDNF is reported to increase neuronal differentiation and neurite outgrowth of progenitor cells in vitro (Palmer et al., 1997; Takahashi et al., 1998). In addition, intraventricular infusion of BDNF is reported to increase neurogenesis in the adult olfactory bulb [Emphasis added _ ed.] (Zigova et al., 1998). Yet another possibility is insulin-like growth factor (IGF-1), a growth-promoting peptide hormone that has neurotrophic properties. IGF-1 increases proliferation and survival of neurons in adult rat (Aberg et al., 2000), although antidepressant regulation of this factor has not been demonstrated. Studies are currently underway to examine the role of the cAMP response element-binding protein and BDNF, as well as other factors, in the upregulation of cell proliferation in response to antidepressant treatment.

The experimental antidepressant NSI-189 is a small molecule drug formulated specifically to stimulate neurogenesis in the human brain.

Neurogenesis in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans.7 Treatment with antidepressant drugs increases hippocampal neurogenesis, and it has been hypothesized that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs.7, 8 Therefore, an accumulating body of evidence strongly supports the hypothesis that a platform of pre-clinical neurogenesis paired with confirmatory behavioral assays may be useful as a drug discovery strategy.

… The study results are consistent with the growing body of evidence that treatment with antidepressant drugs increases hippocampal neurogenesis and with the hypothesis that pre-clinical neurogenesis matched with confirmatory behavioral assays may be useful as a drug discovery strategy…

… In summary, consistent with findings from our group that a neurogenic combination therapy was more effective than placebo in MDD,24 a novel neurogenic compound, NSI-189, has shown promise as a potential treatment for MDD in a Phase 1B, double-blind, randomized, placebo controlled, multiple-dose study with three ascending cohorts. __ Molecular Psychiatry advance online publication 8 December 2015; doi: 10.1038/mp.2015.178

Another class of drugs being developed to aid human cognition — the Ampakines — have also been found to act as a neurotrophic factor, and to promote neurogenesis.

Useful 2014 review article on Ampakines by Gary Lynch at Irvine

The US DARPA has been involved in funding the neurogenic antidepressant NSI-189, and was also involved in early funding (2005) of ampakine CX-717.

More on the difficulties of ampakines in jumping the many and vague hurdles placed in its way by the US FDA.

Given the neuroprotective effect of ampakines, it would seem that DARPA would want to consider making these drugs available to combat troops subject to brain injuries due to concussive effects, such as IEDs. Given the high cost of depression to the military services, DARPA’s reasons for funding NSI-189 are quite obvious. But the possibiolity neuroprotection from brain injury would seem to be just as valid a reason for DARPA funding of ampakines.

Positive allosteric modulators of α-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate (AMPA)–type glutamate receptors (“ampakines” and functionally related compounds) constitute a relatively new class of psychoactive drugs that enhance fast, excitatory transmission in the brain. Because of this effect, ampakines reduce the threshold for inducing memoryrelated changes to synapses and improve learning in animals across species and paradigms. While most CNS drugs target neurons that project in a onestep, parallel fashion to a multitude of sites, ampakine-type agents act on the multiple connections found in serial brain networks. This results in a multiplier effect for the drug, likely to be most pronounced in the elaborate circuits found in the cortex, thereby intensifying cortical regulation of lower brain areas (“pharmacological encephalization”). Evidence that the compounds are effective in animal models of psychiatric disorders associated with abnormal brainstem activity is in agreement with this hypothesis. The possibility that expanding cortical networks will lead to cognitive, as opposed to memory, enhancement in normal brains is largely unexplored. Finally, positive modulators increase the production of brain growth factors that promote plasticity and neuronal viability; upregulation is associated with neuroprotection, growth, and improved functional outcomes in different disease models.

… There is also considerable confusion about the duration of drug action needed to initiate BDNF production. Much of the work with animal models used an ampakine with a half-life of less than 15 minutes, and yet caused substantial increases in BDNF and positive effects in several animal models of intellectual disability. This raises the possibility that minimizing drug half-life might be a useful step towards reducing side effects of type B compounds. To conclude, while much has been accomplished, further progress will likely benefit from recognition of the unique complexities created by increasing excitatory transmission and the implementation of new analytical tools.
__ Medicographia. 2014;36:372-382

Research that results in treatments that amplify the generation of newer and more functional brain circuits — and that protect the function of existing brain circuits against injury — have the potential to be disruptive, in the better sense of the word.

Global Depression Prevalence https://www.washingtonpost.com/news/worldviews/wp/2013/11/07/a-stunning-map-of-depression-rates-around-the-world/

Global Depression Prevalence
Afghanistan, Honduras and the Palestinian territories are the three most-depressed areas researchers looked at.
https://www.washingtonpost.com/news/worldviews/wp/2013/11/07/a-stunning-map-of-depression-rates-around-the-world/

No wonder so many suicide-bombers come from the Muslim lands: Those people are depressed up to their eyeballs — even the youth!


Cynical and opportunistic Muslim clerics and activists who induce depressed and deeply programmed young Muslums to become suicide bombers should be shot, stoned, hanged, burnt at the stake, drawn and quartered, tortured, then killed with extreme prejudice. But that’s just my point of view. Others may wish to omit one or two steps in the process — as long as the final step is carried out.

The Muslim depression pandemic illustrates in yet another reason why the airdrop of inexpensive misoprostol into primitive tribal Muslim lands might help not only downtrodden Muslim women and girls, but the entire Islamic community.

More:

A new and intriguing approach to rescuing brains from Alzheimer’s, illustrating the need to take a massively mult-pronged approach to the human cognition problem.

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