NEUROPROTECTION

GUEST AUTHOR

ZEBA SALEEM

AJMAL KHAN TIBBIYA COLLEGE

ALIGARH

INTRODUCTION

• Glaucoma is a multifactorial neurodegenerative disorder. There is chronic loss of retinal ganglion cells (RGCs) and their axons in this condition. It is hoped that interventions involving neuromodulation (preserving neuronal structure/function), neuroprotection (preventing further neuronal damage) and neuro-regeneration (re-growth of damaged cells/neurons) could be utilized to manage this fearfully blinding disease. 

• Neuroprotection in glaucoma refers to any intervention intended to protect the optic nerve or prevent the death of RGCs, in addition to and as a separate effect from lowering of IOP. 

• This blog post reviews the pharmacological basis of neuroprotection in glaucoma.

PHARMACOLOGICAL APPROACHES TO NEUROPROTECTION

NMDA receptor antagonists:

• Excess glutamate leads to NMDA receptor overactivity and excitotoxicity.
• Initial experiments involved MK-801 (Dizocilpine).
• It completely blocks normal glutamatergic neurotransmission (required for normal CNS function).
• Experiments have shown MK-801 to be neuroprotective by decreasing expression of Bad and transient deactivation of the pro-survival kinase Akt pathway.
• However, since MK-801 is a non-specific blocker of glutamatergic neurotransmission it is not appropriate for clinical use. 
• Memantine is a non-competitive, low-affinity open channel NMDA blocker.
• It exhibits selective blockade of excessively open channels with a fast off-rate.
• It inhibits excessive NMDA receptor activity, while maintaining neoronal cell function.
• It does not accumulate significantly within the channel.
• However, a phase 3 clinical trial on memantine in OAG did not meet its primary end point.

Neurotrophic factors:

• Experimentally neurotrophic factors such as BDNF and CNTF have been reported to enhance survival of RGCs (in optic nerve crush injury models).
• A combination of BDNF and LINGO-1 antagonist has been experimentally shown to enhance long term RGC viability.
• In vitro application of BDNF to isolated RGCs prolongs their survival. In vivo RGC survival is also found to be prolonged by intravitreal injection of BDNF.

Anti-apoptotic agents:

• Supplements of creatine, alpha-Lipoic acid, nicotinamide and epigallocatechin-gallate (EGCG) act by countering oxidative stress, promote mitochondrial function and confer neuroprotection.
• Inhibition of apoptosis can be achieved by 2 mechanisms=

1. Activation of anti-apoptotic extracellular signal regulated kinase (ERK) and Akt by Brimonidine. These enhance the production of Bcl-2 and Bcl-xL.
2. Blocking of apoptotic machinery by the use of caspase inhibitors. Caspases are a family of aspartate-specific cysteine proteases. The term caspase denotes the Cysteine requiring ASPartate proteASE activity of these enzymes.

• Calpeptin, a calpain-specific inhibitor, has been studied for its role in neuroprotection. It prevents Ca++ influx, proteolytic activities and apoptosis in RGC cells.

Nitric oxide synthase antagonists:

• NOS inhibitors such as 2-aminoguanidine, I-NOS and L-N6-(1-iminoethyl) lysine 5-tetrazole amide have been studied for their neuroprotective role.
• Nipradiol, a beta- and alpha1- antagonist was also found to be neuroprotective.
• However, others have reported an absence of NOS release by astrocytes and did not find any neuroprotective effect of amino-guanidine.

Anti-oxidants:

• Anti-oxidants and free radical scavengers reduce RGC death occurring from NMDA toxicity.
• Vitamins C, E, superoxide dismutase, catalase, Ginkgo biloba (EGb 761) have been shown to have these properties.
• Ginkgo biloba also preserves mitochondrial metabolism and enhances ATP production in various tissues.

Calcium channel blockers:

• Nifedipine and Verapamil confer neuroprotection by enhancing OBF. They also improve glutamate metabolism and are responsible for homeostasis in the ONH.
• On the downside, these Ca++ channel blockers cause systemic hypotension which may aggravate retinal ischemia.
• In a rat model, continuous treatment with candesartan (angiotensin II type I receptor blocker) provided significant neuroprotection.

Gene therapy:

• Deprenyl (a monoamine oxidase inhibitor) increases gene expression of factors that halt apoptosis.
• Flunarizine and aurintricarboxylic acid were found to retard apoptosis following light-induced photoreceptor cell death.

Immunomodulators and vaccination:

• Glaucoma can be regarded as an immunogenic mechanism with prominent activation of resident and systemic immune responses during the early course of the disease. 
• Chronic glial activation is regarded as a hallmark of neuroinflammation in glaucoma.
• Associated failure in regulation of immune response pathways may lead to a neurodegenerative state and promote injury to neurons.
• Adaptive/protective responses of resident or systemic immune cells can support neurons and promote tissue repair mechanisms after injurious insults.
• Glatiramer acetate= A non-biological complex heterogeneous mixture of synthetic polypeptides. Peptide epitopes in Glatiramer acetate compete with autoantigens for binding with major histocompatibility complex molecules or antigen-presenting cells, thereby altering the functional outcome of T-cells signaling from inflammatory to anti-inflammatory responses.
• Pharmaceutical inhibition of TNF-a, a major pro-inflammatory and pro-apoptotic cytokine has provided protection against RGC and axonal degeneration in experimental models of glaucoma.
• Selective inhibition of TLR4 signaling with  TAK-242 (resatorvid) has been found to reduce astrocyte activation and RGC death after ON crush injury in mice.
• Inactivation of astroglial NF-kB the key transcriptional activator of inflammatory mediators downstream of TNF-a/TNFR and TLR signaling pathways has reduced the pro-inflammatory genes and promoted RGC survival after retinal ischemia.
• Intraocular administration of cAMP phosphodiesterase inhibitor (Ibudilast) has resulted in decreased production of pro-Iflammatory mediators and increased survival of neurons in Ocular hypertensive rat eyes.

Geranylgeranylacetone (GGA):

• GGA has been observed to evoke the synthesis of HDP70, this could have a neuroprotective role.

Stem cell therapies:

• Stem cells are thought to exert neuroprotective effects by generating neurotrophic factors, modulating MMP and other aspects of the CNS environment that may promote endogenous healing.
• Granulocyte-Colony stimulating factor (G-CSF) is greatly expressed by RGCs and may provide neuroprotection.
• Oligodendrocyte precursor cells (OPCs), a type of neural stem cell, may provide protection to RGCs.
• Mesenchymal stem-cell derived exosomes have been reported to deliver trophic and immunomodulatory factors, suppress the migration of inflammatory cells, attenuate pro-inflammatory cytokine secretion and promote RGC survival. 

Bioenergetics:

• It is the study related to metabolic processes  leading to energy utilization in the form of ATP molecules.
• Energy failure and mitochondrial dysfunction in the ONH may have a role in glaucoma due to reduced energy and increased free radical production.
• Enhanced mitochondrial function or increasing energy supply of neurons may provide neuroprotection.