Blocking Cell Death For True neuroprotection

[Neuroprotection]

Hi all,
I want to apologise in advance for the fact I can?t post links to studdies due to my blindness
Also, just want to say I have been obsessed with the following topic for years and hope to get as many people on bord as possible, I feel it has the potential to transform our lives.
Cell death, most notably apoptosis and necrosis have both beneficial and detrimental affects in the body and especially in the brain, where it plays an important role in development and neurodegeneration.
My interest is in the role of apoptosis and necrosis in learning, memory and drug abuse/addiction.
I would like to start and encourage a theoretical discussion about the possible inhibition, by small molecules, of these pathways and if this could lead to extraordinary nootropic, neuroprotective or other medically relevant affects.
Through my research, I have found that blocking one cell death pathway can activate another, e.g. Caspase3 inhibition blocks apoptosis but can exacerbate necrosis. On the other hand, blocking RIPK1, involved in necrosis can lead to apoptosis. Therefore in my opinion, (Im no biology expert so please correct me if im wrong) it is important to target the final affector of most cell death pathways, the mitochondrial Permiability Transition Pore (MPTP).
I have read that blockade of the MPTP by cyclosporinA analogs which lack immuno-suppression, can trigger intence neuronal stem cell proliferation and neurogenesis as well as protection of mature neurons from insults ranging from protein agrigates to heavy metals and neurotoxic drugs.
What are your thoughts.
I would very much welcome imput from any specialists in the field of cell death.
What are your opinions on the risks and benefits of blocking cell death for short time periods to protect against neurotoxic drugs e.g. methamphetamine or in those suffering strokes or other brain injuries?
Thanks

 

[CFC]

Ah, so you mean acute (eg duration of a drugs binge) and not chronic treatment?

Because afaik the main thrust of interest at the moment is on the clearance of malfunctioning/senescent cells, which appears to rather effectively permit neurogenesis and recovery without the risks associated with preserving cells with failing mitochondria or damaged DNA.

 

[Neuroprotection]

exactly, I am thinking of short term use especialy in conjunction with drugs like amphetamines but also possibly as an protective measure during sedative/hypnotic and alcohol withdrawal to protect against excitotoxicity.
Other possible applications include treatment/reversel of psychotic disorders, as well as co-administration with general anesthetics particularly in children, to prevent the learning and memory impairments that result from neuronal apoptosis.
I realy believe this is an under studied area of research that could save millions from suffering unnecessarily.

 

[sekio]

part of why cell death occurs is due to normal natural factors, eg. many damaged cells will undergo apoptosis instead of becoming cancerous, also synaptic pruning is important in brain development.

another thing to remember is that blocking cell death does not necessarily mean that cells will function 100% as long as they are living. drugs like methamphetamine cause oxidative stress/free radial generation (peroxide, superoxide, hydroxyl etc radicals) which is more of a general toxicant than a specific targeted poison & can damage everything from the cell walls to the DNA in the nucleus ...

as far as my knolwedge goes there is no miracle substance which renders cells immortal and also immune to any form of environmental insult/pressure... of course you could argue carcinogen/mutagenic agents can make cells "immortal" by making them reproduce uncontrollably, but even then competition for resources can pressure those into death, whereas organisms that can tolerate high levels of physical/environmental stress or extreme resource deprivation tend to either change form or become quiescent

 

[Neuroprotection]

You make many fantastic points with a lot of detale so thanks for this.
In regards to free radicals damaging cells, this is why I am particularly interested in blocking the 'mitochondrial permeability transition pore' since doing so dramatically reduces ROS while dramatically enhancing ATP synthesis. Off course I still think this should only be done on a temporary bases, but only when it is established that cell death following a particular drug/event is un necessary and not part of homeostasis.
I believe this is known as Alastasis.
A slightly off topic example of such a process would be opioid or benzodiazepine tolerance/ dependence syndromes, which are due to the body imposing counter-regulatory mechanisms that far outlast the impact on receptor expression/sensitivity. There doesn't appear to be an advantage for the body to induce a severe and protracted withdrawal syndrome which in the case of benzodiazepines likely results in excitotoxicity.
It is true that some neuroprotective therapies e.g. IGF1 may worsen trormatic brain injury by promoting growth of alternative networks that go on to induce epileptogenesis, so it is important to carefully consider all factors before employing a cell survival stratigy.
What are your opinions on viability of temporarily blocking the mitochondrial Transition pore given that it dramatically reduces ROS while promoting cellular survival and boosts energy production?

 

[Neuroprotection]

Interesting sidenote

In a study entitled 'The tangled circotry Of Metabolism And Apoptosis', there is a section on the anti apoptotic members of the BCL2 family. It was argued that up to 80% of their anti apoptotic function was not due to sympley blocking pro apoptotic factor release as previously thought.
Rather, it was shown that they enhanced a process by which a proton gradient could drive ATP synthesis avoiding loss of energy as heat as with proton leakage or free radical generation caused by electron leakage, something very common with the normal operation of the citric acid cycle.

 

[Neuroprotection]

I really hope more people take an interest in this topic.
It has greate potential but is also easily achievable if more people work on it.